Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia

ABSTRACT

There is herein provided a compound of formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage filing, under 35 U.S.C. §371(c), of International Application No. PCT/GB2018/052594, filed onSep. 13, 2018, which claims priority to United Kingdom PatentApplication No. 1714734.9, filed on Sep. 13, 2017.

FIELD OF THE INVENTION

The present invention relates to novel compounds and compositions, andtheir use in the treatment of hyperglycaemia and disorders characterisedby hyperglycaemia, such as type 2 diabetes. In particular, the inventionrelates to novel compounds, compositions and methods for the treatmentof conditions such as type 2 diabetes through activation of theβ₂-adrenergic receptor. Importantly, such compounds are thought to havea beneficial side-effect profile as they do not exert their effectthrough significant cAMP release.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Hyperglycaemia, or high blood sugar is a condition in which an excessiveamount of glucose circulates in the blood plasma. If not treated,hyperglycaemia can be a serious problem, potentially developing intolife-threatening conditions such as ketoacidosis. For example, chronichyperglycemia may cause injury to the heart, and is strongly associatedwith heart attacks and death in subjects with no coronary heart diseaseor history of heart failure. There are various causes of hyperglycaemia,including diabetes and severe insulin resistance.

Severe insulin resistance (SIR) is a condition wherein the patentexperiences very low levels of (or, in extreme cases, no significant)response to insulin. There are several syndromes characterized by SIR,including Rabson-Mendenhall syndrome, Donohue's syndrome(leprechaunism), Type A and Type B syndromes of insulin resistance, theHAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans)syndrome, pseudoacromegaly, and lipodystrophy. The majority of theseconditions have genetic causes, such as mutations in the insulinreceptor gene. The prevalence for Donohue's syndrome, Rabson-Mendenhallsyndrome and Type A syndrome of insulin resistance, has been reported tovary from about 50 reported cases to 1 in 100,000. However, since somediseases are severe and extremely rare, it is likely that many patientsdo not get diagnosed before they die, particularly in less developedareas of the world. Thus, the exact number of patients with thesesyndromes is difficult to assess.

The current standard for hyperglycaemia treatment in patients having SIRis a controlled diet, supplemented with drugs affecting insulin receptorsensitivity, such as metformin, or insulin supplement. However,particularly for disorders caused by mutations in the insulin receptorgene, this treatment is not sufficiently effective and ultimately provesunsuccessful.

Diabetes comprises two distinct diseases, type 1 (or insulin-dependentdiabetes) and type 2 (insulin-independent diabetes), both of whichinvolve the malfunction of glucose homeostasis. Type 2 diabetes affectsmore than 400 million people in the world and the number is risingrapidly. Complications of type 2 diabetes include severe cardiovascularproblems, kidney failure, peripheral neuropathy, blindness and, in thelater stages of the disease, even loss of limbs and, ultimately death.Type 2 diabetes is characterized by insulin resistance in skeletalmuscle and adipose tissue, and there is presently no definitive cure.Most treatments used today are focused on remedying dysfunctionalinsulin signalling or inhibiting glucose output from the liver but manyof those treatments have several drawbacks and side effects. There isthus a great interest in identifying novel insulin-independent ways totreat type 2 diabetes.

In type 2 diabetes, the insulin-signalling pathway is blunted inperipheral tissues such as adipose tissue and skeletal muscle. Methodsfor treating type 2 diabetes typically include lifestyle changes, aswell as insulin injections or oral medications to regulate glucosehomeostasis. People with type 2 diabetes in the later stages of thedisease develop ‘beta-cell failure’ i.e. the inability of the pancreasto release insulin in response to high blood glucose levels. In thelater stages of the disease patients often require insulin injections incombination with oral medications to manage their diabetes. Further,most common drugs have side effects including downregulation ordesensitization of the insulin pathway and/or the promotion of lipidincorporation in adipose tissue, liver and skeletal muscle. There isthus a great interest in identifying novel ways to treat metabolicdiseases including type 2 diabetes that do not include these sideeffects.

Following a meal, increased blood glucose levels stimulate insulinrelease from the pancreas. Insulin mediates normalization of the bloodglucose levels. Important effects of insulin on glucose metabolisminclude facilitation of glucose uptake into skeletal muscle andadipocytes, and an increase of glycogen storage in the liver. Skeletalmuscle and adipocytes are responsible for insulin-mediated glucoseuptake and utilization in the fed state, making them very importantsites for glucose metabolism.

The signalling pathway downstream from the insulin receptor has beendifficult to understand in detail. In brief, control of glucose uptakeby insulin involves activation of the insulin receptor (IR), the insulinreceptor substrate (IRS), the phosphoinositide 3-kinase (PI3K) and thusstimulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), themammalian target of rapamycin (also called the mechanistic target ofrapamycin, mTOR), Akt/PKB (Akt) and TBC1 D4 (AS160), leading totranslocation of the glucose transporter 4 (GLUT4) to the plasmamembrane. Akt activation is considered necessary for GLUT4translocation.

It should be noted that skeletal muscles constitute a major part of thebody weight of mammals and have a vital role in the regulation ofsystemic glucose metabolism, being responsible for up to 85% ofwhole-body glucose disposal. Glucose uptake in skeletal muscles isregulated by several intra- and extracellular signals. Insulin is themost well studied mediator but others also exist. For example, AMPactivated kinase (AMPK) functions as an energy sensor in the cell, whichcan increase glucose uptake and fatty acid oxidation. Due to the greatinfluence skeletal muscles have on glucose homeostasis it is plausiblethat additional mechanisms exist. In the light of the increasedprevalence of type 2 diabetes, it is of great interest to find andcharacterize novel insulin-independent mechanisms to increase glucoseuptake in muscle cells.

Blood glucose levels may be regulated by both insulin andcatecholamines, but they are released in the body in response todifferent stimuli. Whereas insulin is released in response to the risein blood sugar levels (e.g. after a meal), epinephrine andnorepinephrine are released in response to various internal and externalstimuli, such as exercise, emotions and stress, and also for maintainingtissue homeostasis. Insulin is an anabolic hormone that stimulates manyprocesses involved in growth including glucose uptake, glycogen andtriglyceride formation, whereas catecholamines are mainly catabolic.

Although insulin and catecholamines normally have opposing effects, ithas been shown that they have similar actions on glucose uptake inskeletal muscle (Nevzorova et al., Br. J. Pharmacol, 137, 9, (2002)). Inparticular, it has been reported that catecholamines stimulate glucoseuptake via adrenergic receptors (Nevzorova et al., Br. J. Pharmacol,147, 446, (2006); Hutchinson, Bengtsson Endocrinology 146, 901, (2005))to supply muscle cells with an energy-rich substrate. Thus it is likelythat in mammals, including humans, the adrenergic and the insulinsystems can work independently to regulate the energy needs of skeletalmuscle in different situations. Since insulin also stimulates manyanabolic processes, including some that promote undesired effects suchas stimulation of lipid incorporation into tissues, leading to e.g.obesity, it would be beneficial to be able to stimulate glucose uptakeby other means; for example, by stimulation of the adrenergic receptors(ARs).

All ARs are G protein-coupled receptors (GPCRs) located in the cellmembrane and characterized by an extracellular N-terminus, followed byseven transmembrane α-helices (TM-1 to TM-7) connected by threeintracellular (IL-1 to IL-3) and three extracellular loops (EL-1 toEL-3), and finally an intracellular C-terminus. There are threedifferent classes of ARs, with distinct expression patterns andpharmacological profiles: α₁-, α₂- and β-ARs. The α₁-ARs comprise theα_(1A), α_(1B) and α_(1D) subtypes while α₂-ARs are divided into α_(2A),α_(2B) and α_(2c). The β-ARs are also divided into the subtypes β₁, β₂,and β₃, of which β₂-AR is the major isoform in skeletal muscle cells.ARs are G protein coupled receptors (GPCRs) that signal throughclassical secondary messengers such as cyclic adenosine monophosphate(cAMP) and phospholipase C (PLC).

Many effects occurring downstream of ARs in skeletal muscles have beenattributed to classical secondary messenger signalling, such as increasein cAMP levels, PLC activity and calcium levels. Stimulation involvingthe classical secondary messengers has many effects in differenttissues. For example, it increases heart rate, blood flow, airflow inlungs and release of glucose from the liver, which all can bedetrimental or be considered unwanted side effects if stimulation of ARsshould be considered as a type 2 diabetes treatment. Adverse effects ofclassical AR agonists are, for example, tachycardia, palpitation,tremor, sweats, agitation and increased glucose levels in the blood(glucose output from the liver). It would thus be beneficial to be ableto activate ARs without activating these classical secondary messengers,such as cAMP, to increase glucose uptake in peripheral tissues withoutstimulating the unwanted side effects.

Glucose uptake is mainly stimulated via facilitative glucosetransporters (GLUT) that mediate glucose uptake into most cells. GLUTsare transporter proteins that mediate transport of glucose and/orfructose over the plasma membrane down the concentration gradient. Thereare fourteen known members of the GLUT family, named GLUT1-14, dividedinto three classes (Class I, Class II and Class III) dependent on theirsubstrate specificity and tissue expression. GLUT1 and GLUT4 are themost intensively studied isoforms and, together with GLUT2 and GLUT3,belong to Class I which mainly transports glucose (in contrast to ClassII that also transports fructose). GLUT1 is ubiquitously expressed andis responsible for basal glucose transport. GLUT4 is only expressed inperipheral tissues such as skeletal muscle, cardiac muscle and adiposetissues. GLUT4 has also been reported to be expressed in, for example,the brain, kidney, and liver. GLUT4 is the major isoform involved ininsulin stimulated glucose uptake. The mechanism whereby insulinsignalling increases glucose uptake is mainly via GLUT4 translocationfrom intracellular storage to the plasma membrane. It is known thatGLUT4 translocation is induced by stimulation of the β₂-adrenergicreceptor.

Thus, a possible treatment of a condition involving dysregulation ofglucose homeostasis or glucose uptake in a mammal, such as type 2diabetes, would involve the activation of the β₂-adrenergic receptorleading to GLUT4 translocation to the plasma membrane and promotion ofglucose uptake into skeletal muscle leading to normalization of wholebody glucose homeostasis. In addition, it would be advantageous if thetreatment does not involve signalling through cAMP as this would lead toa favourable side-effect profile.

The vasodilator 4-(2-(butylamino)-1-hydroxyethyl)phenol, which has beenused in the treatment of peripheral vascular disorders, has been foundto initially increase blood sugar and has been contraindicated indiabetes and pre-diabetes (see Unger, H., Zeitschrift for die GesamteInnere Medizin und Ihre Grenzgebiete, 16, 742 (1961)).

DESCRIPTION OF THE INVENTION

We have now surprisingly found that certain fluoro substitutedβ-hydroxyethylamines acting as agonists at the β₂-adrenergic receptorincrease glucose uptake in skeletal muscle.

In addition, we have found that this effect is not mediated throughsignificant cAMP release, such that many of the commonly described sideeffects seen with traditional β₂-adrenergic agonists (e.g. tachycardia,palpitation, tremor, sweats, agitation, and the like) can be reduced.

The use of such compounds in medicine represents a promising strategyfor the treatment of conditions characterized by high blood sugar levels(i.e. hyperglycaemia), such as type 2 diabetes.

Compounds of the Invention

In a first aspect of the invention, there is provided a compound offormula I

or a pharmaceutically acceptable salt thereof, wherein:

R¹ represents C₄₋₁₂ alkyl optionally substituted by one or more halo;

R² and R³ each independently represent H or C₁3 alkyl optionallysubstituted by one or more halo;

or R² and R³ may be linked together to form, together with the carbonatom to which they are attached, a 3- to 6-membered ring, which ringoptionally is substituted by one or more groups independently selectedfrom halo and C₁ alkyl optionally substituted by one or more halo;

each X independently represents Cl, Br, R^(a), —CN, —N₃, —N(R^(b))R^(c),—NO₂, —ONO₂, —OR^(d), —S(O)_(p)R^(e) or —S(O)_(q)N(R^(f))R^(g−);

R^(a) represents C₁₋₆ alkyl optionally substituted by one or more groupsindependently selected from G;

each R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) independentlyrepresents H or C₁₋₆ alkyl optionally substituted by one or more groupsindependently selected from G;

or alternatively any of R^(b) and R^(c) and/or R^(f) and R^(g) may belinked together to form, together with the nitrogen atom to which theyare attached, a 4- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from halo, C₁₋₃ alkyl optionallysubstituted by one or more halo, and ═O;

G represents halo, —CN, —N(R^(a1))R^(b1), —OR¹, —S(O)_(p)R^(d1),—S(O)_(q)N(R^(e1))R^(f1) or ═O;

each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1) and R¹¹ independentlyrepresents H or C₁₋₆ alkyl optionally substituted by one or more halo;

or alternatively any of R^(a1) and R^(b1) and/or R^(e1) and R¹¹ may belinked together to form, together with the nitrogen atom to which theyare attached, a 4- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from halo, C₁₋₃ alkyl optionallysubstituted by one or more halo, and ═O;

m represents 1 to 5;

n represents 0 to 4;

with the proviso that the sum of m and n is equal to, or less than, 5;

each p independently represents 0, 1 or 2; and each q independentlyrepresents 1 or 2;

which compounds (including pharmaceutically acceptable salts) may bereferred to herein as the “compounds of the invention”.

For the avoidance of doubt, the skilled person will understand thatreferences herein to compounds of particular aspects of the invention(such as the first aspect of the invention, e.g. compounds of formula I)will include references to all embodiments and particular featuresthereof, which embodiments and particular features may be taken incombination to form further embodiments.

Unless indicated otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention pertains.

Pharmaceutically acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound ofthe invention with one or more equivalents of an appropriate acid orbase, optionally in a solvent, or in a medium in which the salt isinsoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound ofthe invention in the form of a salt with another counter-ion, forexample using a suitable ion exchange resin.

Particular acid addition salts that may be mentioned include carboxylatesalts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate,heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate,propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate,α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate,phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxy-benzoate, salicylate, nicotinate, isonicotinate, cinnamate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts),halide salts (e.g. chloride, bromide or iodide salts), sulphonate salts(e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate,xylenesulphonate, methanesulphonate, ethanesulphonate,propanesulphonate, hydroxy-ethanesulphonate, 1- or2-naphthalene-sulphonate or 1,5-naphthalenedisulphonate salts) orsulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphateor nitrate salts, and the like.

Particular base addition salts that may be mentioned include saltsformed with alkali metals (such as Na and K salts), alkaline earthmetals (such as Mg and Ca salts), organic bases (such as ethanolamine,diethanolamine, triethanolamine, tromethamine and lysine) and inorganicbases (such as ammonia and aluminium hydroxide). More particularly, baseaddition salts that may be mentioned include Mg, Ca and, mostparticularly, K and Na salts.

For the avoidance of doubt, compounds of the first aspect of theinvention may exist as solids, and thus the scope of the inventionincludes all amorphous, crystalline and part crystalline forms thereof,and may also exist as oils. Where compounds of the first aspect of theinvention exist in crystalline and part crystalline forms, such formsmay include solvates, which are included in the scope of the invention.Compounds of the first aspect of the invention may also exist insolution.

Compounds of the first aspect of the invention may contain double bondsand may thus exist as E (entgegen) and Z (zusammen) geometric isomersabout each individual double bond. All such isomers and mixtures thereofare included within the scope of the invention.

Compounds of the first aspect of the invention may also exhibittautomerism. All tautomeric forms and mixtures thereof are includedwithin the scope of the invention.

Compounds of the first aspect of the invention may also contain one ormore asymmetric carbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers (i.e. enantiomers) may be isolated by separationof a racemic or other mixture of the compounds using conventional, e.g.fractional crystallisation or HPLC, techniques. Alternatively thedesired optical isomers may be obtained from appropriate opticallyactive starting materials under conditions which will not causeracemisation or epimerisation (i.e. a ‘chiral pool’ method), by reactionof the appropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution); for example, with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

As used herein, references to halo and/or halogen groups will eachindependently refer to fluoro, chloro, bromo and iodo (for example,fluoro (F) and chloro (Cl)).

Unless otherwise specified, C_(1-z) alkyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of three) of carbon atoms, bebranched-chain, and/or cyclic (so forming a C_(3-z)-cycloalkyl group).When there is a sufficient number (i.e. a minimum of four) of carbonatoms, such groups may also be part cyclic. Part cyclic alkyl groupsthat may be mentioned include cyclopropylmethyl and cyclohexylethyl.When there is a sufficient number of carbon atoms, such groups may alsobe multicyclic (e.g. bicyclic or tricyclic) or spirocyclic. Such alkylgroups may also be saturated or, when there is a sufficient number (i.e.a minimum of two) of carbon atoms, be unsaturated (forming, for example,a C_(2-z) alkenyl or a C_(2-z) alkynyl group). Particular alkyl groupsthat may be mentioned include saturated alkyl groups.

For the avoidance of doubt, as used herein, references to heteroatomswill take their normal meaning as understood by one skilled in the art.Particular heteroatoms that may be mentioned include phosphorus,selenium, tellurium, silicon, boron, oxygen, nitrogen and sulphur (e.g.oxygen, nitrogen and sulphur).

For the avoidance of doubt, references to polycyclic (e.g. bicyclic ortricyclic) groups (e.g. when employed in the context of cycloalkylgroups) will refer to ring systems wherein at least two scissions wouldbe required to convert such rings into a straight chain, with theminimum number of such scissions corresponding to the number of ringsdefined (e.g. the term bicyclic may indicate that a minimum of twoscissions would be required to convert the rings into a straight chain).For the avoidance of doubt, the term bicyclic (e.g. when employed in thecontext of alkyl groups) may refer to groups in which the second ring ofa two-ring system is formed between two adjacent atoms of the firstring, and may also refer to groups in which two non-adjacent atoms arelinked by an alkylene group, which later groups may be referred to asbridged.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.in which one or more hydrogen atoms are replaced by the hydrogen isotopedeuterium.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent. For example, in the situation in which two or more Xgroups are present, those X groups may be the same or different.Similarly, where two or more X groups are present and each representhalo, the halo groups in question may be the same or different.Likewise, when more than one R^(a) is present and each independentlyrepresents C₁₋₆ alkyl substituted by one or more G group, the identitiesof each G are in no way interdependent.

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation, e.g. from a reaction mixture, to a usefuldegree of purity.

All embodiments of the invention and particular features mentionedherein may be taken in isolation or in combination with any otherembodiments and/or particular features mentioned herein (hencedescribing more particular embodiments and particular features asdisclosed herein) without departing from the disclosure of theinvention.

In particular embodiments of the first aspect of the invention, R¹represents C₄₋₁₀ alkyl optionally substituted by one or more halo, suchas C₄₋₈ alkyl optionally substituted by one or more halo.

In particular embodiments of the first aspect of the invention, R¹represents C₄₋₁₀ alkyl optionally substituted by one or more F, such asC₄₋₈ alkyl optionally substituted by one or more F.

In more particular embodiments, R¹ represents C₄₋₁₀ alkyl, such as C₄₋₈alkyl.

In further embodiments, R¹ represents C₄₋₇ alkyl (e.g. C₄₋₅ alkyl). Forexample, R¹ may represent C₄ alkyl (e.g. linear C₄ alkyl) or C₅ alkyl(e.g. branched C₅ alkyl).

In certain embodiments, where R¹ represents C₄₋₁₂ alkyl (e.g. C₄₋₇alkyl, such as C₄₋₅ alkyl) the carbon bound to the essential —NH— groupis unbranched, e.g. represented by a —CH₂— moiety.

In alternative embodiments, where R¹ represents C₄₋₁₂ alkyl (e.g. C₄₋₇alkyl, such as C₄₋₅ alkyl) the carbon bound to the essential —NH— groupis branched, e.g. represented by a —CH(CH₃)— moiety.

Particular R¹ groups that may be mentioned include those in which thealkyl group (e.g. the C₄₋₁₀ alkyl, such as C₄₋₈ alkyl) is linear (e.g.n-butyl, n-hexyl or n-octyl).

Certain further R¹ groups that may be mentioned include those in whichthe alkyl group (e.g. the C₄₋₁₀ alkyl, such as C₄₋₈ alkyl or,particularly, C₄₋₆ alkyl) is linear (e.g. n-butyl, n-hexyl or n-octyl,such as n-butyl), branched (e.g. t-butyl, neopentyl or2-methyl-pentanyl), or cyclic/part-cyclic (e.g. methyl cyclobutyl ormethyl cyclopropyl).

Yet more particular R¹ groups that may be mentioned include those inwhich the alkyl group represents C₄₋₁₂ alkyl (e.g. C₄₋₇ alkyl, such asC₄₋₅ alkyl) wherein the carbon bound to the essential —NH— group issubstituted by one substituent, e.g. represented by a —CH(R⁴)— moiety,wherein R⁴ represents C₁₋₂ alkyl (e.g. methyl), e.g. wherein R¹represents 2-pentyl.

In certain embodiments, R¹ represents n-butyl, tert-butyl or 2-pentyl.

In certain embodiments, R¹ represents 2-pentyl.

In further embodiments that may be mentioned, R¹ represents n-butyl,tert-butyl, 2-pentyl, 2-methyl-pent-2-yl, 1-methyl cyclobutyl, 1-methylcyclopropyl or neopentyl.

In particular embodiments, R¹ does not represent tert-butyl.

For the avoidance of doubt, in certain embodiments R¹ representstert-butyl.

In particular embodiments, R¹ represents a group of structure (i.e.substructure)

wherein:

R^(x), R^(Y) and R^(z) each independently represent H or C₁₋₁₁ alkyl(e.g. C₁ alkyl) optionally substituted by one or more F;

or alternatively R^(x) and R^(z) be linked together to form, togetherwith the carbon atom to which they are attached, a 4- to 6-memberedring, which ring is optionally substituted by one or more F.

As used herein, the skilled person will understand that bondsterminating with

represents the point of attachment (e.g. to the essential N atom incompounds of formula I, including all embodiments thereof).

For the avoidance of doubt, the skilled person will understand that,where R¹ is represented by the substructure bearing R^(x), R^(y) andR^(z) groups, the sum total of carbons presented in the R^(x), R^(y) andR^(z) groups, together with the carbon to which they are attached, maynot exceed those present in the corresponding R¹ groups, as definedherein (including all embodiments thereof).

For the avoidance of doubt, groups forming part of structuresrepresenting R¹ (e.g. R^(x), R^(y) and R^(z), and the carbon to whichthey are attached) may be optionally substituted as defined herein forR¹.

In further particular embodiments, R¹ may represent

wherein R^(x), R^(y) and R^(z) each independently represent H or C₁₋₁₁alkyl, as appropriate.

In more particular embodiments, R¹ may represent

wherein R^(x) and R^(z) each independently represent H or C₁₋₁₁ alkyl,as appropriate (e.g. n-propyl). In particular embodiments, when R^(x)and R^(z) are not H, they may be the same.

In alternative embodiments, when R^(x) and R^(z) are not H, they may bedifferent (e.g. R^(x) may be propyl and R^(z) methyl, i.e. R¹ may be2-pentyl).

In such instances, the skilled person will recognize that the carbon towhich R^(x) and R^(z) is a stereocentre and therefore R¹ may be depictedas

The skilled person will understand that such a stereocentre may bereferred to as being in either the (R) or (S) configuration, dependingon whether R^(x) or R^(z) is assigned a higher priority (according tothe Cahn-Ingold-Prelog system, as understood by those skilled in theart).

In particular such embodiments, R^(x) and R^(z) may each independentlyrepresent C₁₋₁₁ alkyl, wherein R^(x) is a larger alkyl group (i.e. has agreater number of carbons atoms forming said alkyl group) than R^(z).For example, in such embodiments R^(z) may represent C₁₋₂ alkyl andR^(x) may represent C₃₋₁₀ alkyl.

In particular such embodiments, R¹ is a group of structure

such as wherein R^(z) may represent C₁₋₂ alkyl and R^(x) may representC₃₋₈ alkyl.

In particular such embodiments:

R^(z) represents methyl; and/or (e.g. and)

R^(x) represents n-propyl.

In alternative such embodiments, R¹ is a group of structure

such as wherein R^(z) may represent C₁₋₂ alkyl and R^(x) may representC₃₋₈ alkyl.

In particular such alternative embodiments:

R^(z) represents methyl; and/or (e.g. and)

R^(x) represents n-propyl.

In further alternative embodiments, R¹ may represent

wherein R^(x) represents H or C₃₋₉ alkyl, such as n-propyl (i.e. R¹ maybe n-butyl).

The skilled person will understand that the prefixes “n-”, “sec-” and“tert-” when applied to alkyl groups indicate the terms “normaf”,“secondary” and “tertiary”. The term “normal” indicates a linear alkylgroup where the point of attachment of the group to the rest of amolecule is through a carbon atom at the end of the carbon chain andthus that that carbon atom is bound to one other carbon atom. The term“secondary” indicates that the point of attachment of the rest of themolecule to the alkyl group is through a carbon atom adjacent to the endof the carbon chain and thus that that carbon is itself bound to twoother carbon atoms. The term “tertiary” indicates that the point ofattachment of the alkyl group to the rest of a molecule is through acarbon atom that is bound to three other carbon atoms.

In particular embodiments of the first aspect of the invention, each R²and R³ independently represents H or C₁₋₂ alkyl (e.g. methyl).

In further embodiments of the first aspect of the invention, each R² andR³ independently represents H, methyl or ethyl (e.g. methyl).

In more particular embodiments, R² represents H and R³ represents H ormethyl.

In yet more particular embodiments, R² and R³ each represent H.

In certain embodiments of the compounds of the invention, m represents1, 2 or 3. For example, m may represent 1 or 2.

In certain embodiments of the compounds of the invention, when mrepresents 3, the F atoms are located in the 2-, 3- and 4-positions orthe 3-, 4-, 5 positions.

In certain embodiments of the compounds of the invention, when mrepresents 2, the F atoms are located in the 2- and 4-positions, or the3- and 4-positions, or the 3- and 5-positions (e.g. the 3- and4-positions).

In further embodiments, when m represents 2, the F atoms are located inthe 2- and 3-positions, 2- and 4-positions, or the 3- and 4-positions,or the 3- and 5-positions.

In certain embodiments of the compounds of the invention, when mrepresents 1, the F atom is located the 3- or 4-position (e.g. the3-position).

For example, the skilled person will understand that, in certainembodiments, when m represents 2, the F atoms are located in the 3- and4-positions, and when m represents 1, the F atom is located the 3- or4-position (e.g. the 3-position).

In further embodiments, when m represents 1, the F atom is located the2-, 3- or 4-position (e.g. the 3-position).

In certain embodiments of the compounds of the invention, wherein nrepresents 0, 1, 2 or 3, each X independently represents Cl, Br, R^(a),—CN, —N₃, —N(R^(b))R^(c), —NO₂ or —OR^(d), wherein R^(a) represents C₁₋₄alkyl optionally substituted by one or more F, and wherein R^(b), R^(c)and R^(d) each independently represent H or C₁₋₄ alkyl optionallysubstituted by one or more F.

For example, each X may independently represent Cl, Br, R^(a), —CN, —N₃,—N(R^(b))R^(c), —NO₂ or —OR^(d), wherein R^(a) represents C₁₋₄ alkyloptionally substituted by one or more F, and R^(b), R^(c) and R^(d) eachindependently represent H or C₁₋₄ alkyl optionally substituted by one ormore F or ═O.

In further embodiments, each X may independently represent Cl, Br,R^(a), —CN, —N₃, —N(R^(b))R^(c), —NO₂ or —OR^(d), wherein R^(a)represents C₁₋₄ alkyl optionally substituted by one or more F, and R^(b)and R^(c) each independently represent H or C₁₋₄ alkyl optionallysubstituted by ═O, and R^(d) represents H or C₁₋₄ alkyl optionallysubstituted by one or more F.

In more particular embodiments, each X independently represents Cl,R^(a), —N(R^(b))R^(c), —CN or —OH, wherein R^(a) represents C₁₋₄ alkyl(e.g. C₁₋₂ alkyl) optionally substituted by one or more F (for exampleR^(a) represents —CH₃, —CHF₂ or —CF₃ (e.g. —CF₃)), and R^(b) and R^(c)each independently represent H or C₁₋₄ alkyl optionally substituted by═O (for example R^(c) represents —C(O)CH₃).

In yet more particular embodiments, each X independently represents Cl,R^(a), —N(R^(b))R^(c) or —OH, wherein R^(a) represents C₁₋₂ alkyloptionally substituted by one or more F (for example R^(a) represents—CHF₂ or —CF₃ (e.g. —CF₃)), and R^(b) and R^(c) each independentlyrepresent H or C₁₋₄ alkyl optionally substituted by ═O (for exampleR^(c) represents —C(O)CH₃).

In further particular embodiments, each X independently represents Cl,R^(a), —NH₂, —NHC(O)CH₃, —CF₃ or —OH, wherein R^(a) represents C₁₋₂alkyl optionally substituted by one or more F.

In yet further particular embodiments, each X independently representCl, —NH₂, —NHC(O)CH₃, —CF₃ or —OH. In a further embodiment, each Xindependently represents —NH₂, —NHC(O)CH₃ or —OH, such as —NH₂ or—NHC(O)CH₃ (e.g. —NH₂).

In some embodiments of the compounds of the invention, n represents 0, 1or 2 (for example 1 or 2, e.g. 1).

In certain embodiments of the compounds of the invention, n represents0, 1 or 2 (e.g. 0 or 1).

In particular embodiments of the compounds of the invention, nrepresents 1.

In alternative embodiments of the compounds of the invention, nrepresents 0.

In certain embodiments, wherein n represents 2, each X independentlyrepresents Cl, —NH₂, —NHC(O)CH₃, —CF₃ or —OH. In further certainembodiments, wherein n represents 2, each X independently represents—NH₂, —NHC(O)CH₃ or —OH. In such embodiments, the X groups may belocated in the 2- and 3-positions, or the 2- and 4-positions or 3- and5-positions (e.g. 2- and 3-positions) of the essential benzene ring.

In certain embodiments, wherein n represents 1, X represents Cl, R^(a),—NH₂, —NHC(O)CH₃ or —OH wherein R^(a) represents C₁₋₂ alkyl optionallysubstituted by one or more F (e.g. CF₃). In further certain embodiments,wherein n represents 1, X represents Cl, —NH₂, —NHC(O)CH₃ or —OH. Inparticular embodiments, wherein n represents 1, X represents —NH₂,—NHC(O)CH₃ or —OH. In such embodiments, the X group may be located inthe 3-, 4- or 5-position of the essential benzene ring. In further suchembodiments, the X group may also (or instead) be located in the2-position of the essential benzene ring.

In certain embodiments, wherein n represents 1, X represents —NH₂ or—NHC(O)CH₃ (e.g. —NH₂). In such embodiments, the X group may be locatedin the 3- or 4-positions of the essential benzene ring. In further suchembodiments, the X group may be located in the 2- or 3-position (e.g.the two position) of the essential benzene ring.

In certain embodiments, wherein n represents 1, X represents —OH. Insuch embodiments, the X group may be located in the 3-, 4- or 5-positionof the essential benzene ring. In further such embodiments, the X groupmay be located in the 2- or 3-position (e.g. the two position) of theessential benzene ring.

In certain embodiments that may be mentioned, when n represents 2 ormore (i.e. more than one X substituent is present), no more than one Xmay represent a group selected from —N(R^(b))R^(c) and —OR^(d)(particularly where R^(b), R^(c) and R^(d) represent H).

In further embodiments:

m represents 1 or 2 (e.g. 1);

n represents 1;

X represents —NH₂, —NHC(O)CH₃ or —OH;

particularly where the F atoms are located in the 2-, 3-, 4- or5-positions of the essential benzene ring; and

particularly where the X group is in the 3-, 4- and 5-positions of theessential benzene ring.

In particular embodiments that may be mentioned, the sum of m and n doesnot exceed 2.

In further embodiments, there is provided a compound of formula I, or apharmaceutically acceptable salt thereof, wherein the essential benzenering is unsubstituted in the 2-, 3-, 5- and 6-positions. For example, incertain embodiments the essential benzene ring is unsubstituted in the5- and 6-positions.

In particular embodiments of the first aspect of the invention:

m represents 1;

the F atom is located in the 3- or 4-position (e.g. the 3-position) ofthe essential benzene ring; and

n represents 0.

In particular embodiments of the first aspect of the invention:

m represents 1;

the F atom is located in the 3-position of the essential benzene ring;and

n represents 1;

X represents —NH₂, —NHC(O)CH₃ or —OH; and

the X group is in the 4- or 5-positions of the essential benzene ring.

In particular embodiments of the first aspect of the invention:

m represents 1;

the F atom is located in the 4-position of the essential benzene ring;and

n represents 1;

X represents —NH₂, —NHC(O)CH₃ or —OH; and

the X group is in the 3-position of the essential benzene ring.

In particular embodiments of the first aspect of the invention:

m represents 2;

the F atoms are located in the 3- and 5-positions of the essentialbenzene ring; and

n represents 0.

In particular embodiments of the first aspect of the invention:

m represents 2;

the F atoms are located in the 3- and 4-positions of the essentialbenzene ring; and

n represents 0.

In particular embodiments of the first aspect of the invention:

m represents 2;

the F atoms are located in the 2- and 4-position of the essentialbenzene ring;

n represents 1;

X represents —NH₂, —NHC(O)CH₃ or —OH; and

the X group is in the 3-position of the essential benzene ring.

For example, in a particular embodiment of the first aspect of theinvention:

R¹ represents n-butyl;

R² and R³ represent H;

m represents 1;

the F atom is located in the 4-position of the essential benzene ring;

n represents 1; and

X represents —NH₂ and is in the 3-position on the phenyl group to whichit is attached.

Similarly, in a particular embodiment:

R¹ represents tert-butyl;

R² and R³ represent H;

m represents 1; and

the F atom is located in the 3-position of the essential benzene ring.

For the avoidance of doubt, when R¹ represents n-butyl, R² and R³represent H, m represents 1 and the F atom is in the 4-position of theessential benzene ring, and n represents 1, X represents —NH₂ and is inthe 3-position on the essential benzene ring, the compound of formula Imay be depicted as:

In further particular embodiments of the compounds of the invention, thecompound of formula I is a compound of formula IA

wherein R¹, R² and R³ are as defined herein (for the avoidance of doubt,including all embodiments thereof), and Y¹, Y², Y³, Y⁴ and Y⁵ eachindependently represent H, F or X, wherein X is as defined herein (forthe avoidance of doubt, including all embodiments thereof),

with the proviso that at least one of Y¹ to Y⁵ represents F.

In certain embodiments, there is provided a compound of formula IA,wherein:

Y¹ and Y⁵ each independently represent H or F; and

Y², Y³ and Y⁴ each independently represent H, F, R^(a), —CN, —N₃,—N(R^(b))R^(c), —NO₂ or —OR^(d),

wherein R^(a) represents C₁₋₄ alkyl optionally substituted by one ormore F, and wherein R^(b),

R^(c) and R^(d) each independently represent H or C₁₋₄ alkyl optionallysubstituted by one or more F or ═O,

with the proviso that at least one of Y¹ to Y⁵ represents F.

In particular embodiments, there is provided a compound of formula IA,wherein Y¹ and Y³ represent F (e.g. wherein Y² represents X, such as—NH₂ or —NHC(O)CH₃, and Y⁴ and Y⁵ represent H).

In further embodiments, there is provided a compound of formula IA,wherein Y² represents F (e.g. wherein Y³ represents X, such as —NH₂, andY¹, Y⁴ and Y⁵ represent H, or wherein Y¹, Y³, Y⁴ and Y⁵ represent H).

In further embodiments, there is provided a compound of formula IA,wherein either Y², Y³, Y² and Y⁴, or Y² and Y³ represents F, and theremainder of Y¹ to Y⁵ represents H.

In certain embodiments, there is provided a compound of formula IA,wherein one or both (e.g. one) of Y² or Y³ represents a group selectedfrom Cl, F and —OH (e.g. Cl or F, such as F), and the remainder of Y¹ toY⁵ represents H.

In particular embodiments:

Y¹ and Y⁵ each represent H or F; and

Y², Y³ and Y⁴ each independently represent H, F, R^(a), —CN,—N(R^(b))R^(c), or —OH, wherein R^(a) represents C₁₋₂ alkyl optionallysubstituted by one or more F (for example, R^(a) may represent —CH₃,—CF₃ or —CHF₂), and R^(b) and R^(c) each independently represent H orC₁₋₄ alkyl optionally substituted by ═O (for example, R^(c) mayrepresent —C(O)CH₃), with the proviso that one or two of Y¹ to Y⁵represents F.

In further particular embodiments:

Y¹ and Y⁵ each represent H; and

Y², Y³ and Y⁴ each independently represent H, F, —N(R^(b))R^(c), —CN or—OH, wherein R^(b) and

R^(c) each independently represent H or C₁₋₄ alkyl optionallysubstituted by ═O (for example,

R^(c) may represent —C(O)CH₃),

with the proviso that one or two of Y², Y³ and Y⁴ represent F.

In more particular embodiments:

Y¹ and Y⁵ each independently represent H or F; and Y², Y³ and Y⁴ eachindependently represent H, F, —NH₂, —NHC(O)CH₃ or —OH, with the provisothat one or two of Y², Y³ and Y⁴ represent F.

In alternative embodiments:

Y¹ represents H or F;

Y², Y³ and Y⁴ each independently represent F, R^(a), —CN, —N₃,—N(R^(b))R^(c), —NO₂ or —OR^(d); wherein R^(a) represents C₁₋₄ alkyloptionally substituted by one or more F, wherein R^(b), R^(c) and R^(d)each independently represents H or C₁₋₄ alkyl optionally substituted byone or more F or ═O; and

Y⁵ represents H,

with the proviso that one of Y¹ to Y⁴ represents F.

In further alternative embodiments:

Y¹ represents H or F;

Y², Y³ and Y⁴ each independently represent H, F, Cl, —N(R^(b))R^(c) or—OH, wherein R^(b) and R^(c) each independently represent H or C₁₋₄alkyl optionally substituted by ═O.

Y⁵ represents H,

with the proviso that one of Y¹ to Y⁴ represents F.

In yet more particular embodiments:

Y¹ represents H or F;

Y², Y³ and Y⁴ each independently represent H, F, —NH₂, —NHC(O)CH₃ or—OH; and

Y⁵ represents H,

with the proviso that one of Y¹ to Y⁴ represents F.

In yet more particular embodiments:

Y¹, Y² and Y⁵ each represent H; and

Y³ and Y⁴ each independently represent H, F, —NH₂, —NHC(O)CH₃ or —OH,with the proviso that one of Y¹ to Y⁴ represents F.

In yet more particular embodiments:

Y¹, Y², Y³ and Y⁵ represents H; and

Y⁴ represents F.

In yet more particular embodiments:

Y¹, Y², Y⁴ and Y⁵ represents H; and

Y³ represents F.

In alternative embodiments:

Y¹, Y³, Y⁴ and Y⁵ represents H; and

Y² represents F.

In more alternative embodiments:

Y¹ and Y⁵ each represent H;

Y² and Y⁴ each independently represent —NH₂, —NHC(O)CH₃ or —OH and

Y³ represents F.

In yet more alternative embodiments:

Y¹ and Y⁵ each represent H;

Y² and Y⁴ each independently represent H or F; and

Y³ represents —NH₂, —NHC(O)CH₃ or —OH.

In certain embodiments:

Y¹ and Y³ each represent F; and

Y² represents —NH₂ or —NHC(O)CH₃; and

Y⁴ and Y⁵ each represent H.

In further certain embodiments:

Y¹, Y³ and Y⁵ represent H; and

Y² and Y⁴ each represent F.

In alternative certain embodiments:

Y¹, Y⁴ and Y⁵ represent H; and

Y² and Y³ each represent F.

The skilled person will understand that particular X groups (and thepositions and number thereof, such as may correspond to Y¹ to Y⁵ groupsin compounds of formula IA) that may be mentioned include those presentin the examples provided herein.

Similarly, the skilled person will understand that particular R¹, R² andR³ groups that may be mentioned include those present in the examplesprovided herein.

For example, in a particular embodiment of the first aspect of theinvention:

R¹ represents n-butyl or cyclopropylmethyl;

R² and R³ represent H;

m represents 1;

n represent 0; and

the F atom is in the 4-position on the phenyl group to which it isattached (i.e. in a compound of formula IA, Y¹, Y², Y⁴ and Y⁵ representH and Y³ represents —F).

In an alternative example of a particular embodiment of the first aspectof the invention:

R¹ represents n-butyl or cyclopropylmethyl;

R² and R³ represent H;

m represents 1;

n represent 0; and

the F atom is in the 3-position on the phenyl group to which it isattached (i.e. in a compound of formula IA, Y¹, Y³, Y⁴ and Y⁵ representH and Y² represents —F).

In a further example of a particular embodiment of the first aspect ofthe invention:

R¹ represents t-butyl;

R² and R³ represent H;

m represents 1;

n represent 0; and

the F atom is in the 3-position on the phenyl group to which it isattached (i.e. in a compound of formula IA, Y¹, Y³, Y⁴ and Y⁵ representH and Y² represents —F).

Particular compounds of the first aspect of the invention that may bementioned include the compounds of the examples provided herein, andpharmaceutically acceptable salts thereof. Thus, compounds of formula Ithat may be mentioned include:

-   2-(butylamino)-1-(3,5-difluorophenyl)ethan-1-ol-   2-(butylamino)-1-(3,4-difluorophenyl)ethan-1-ol-   1-(4-amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol-   N-(3-(2-(butylamino)-1-hydroxyethyl)-2,6-difluorophenyl)acetamide-   1-(3-amino-2,4-difluorophenyl)-2-(butylamino)ethan-1-ol-   1-(4-amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol

and pharmaceutically acceptable salts thereof.

More particular compounds of formula I include:

-   2-(butylamino)-1-(3,5-difluorophenyl)ethan-1-ol-   2-(butylamino)-1-(3,4-difluorophenyl)ethan-1-ol

and pharmaceutically acceptable salts thereof.

Certain particular compounds of formula I include:

-   1-(4-amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol-   N-(3-(2-(butylamino)-1-hydroxyethyl)-2,6-difluorophenyl)acetamide-   1-(3-amino-2,4-difluorophenyl)-2-(butylamino)ethan-1-ol-   1-(4-amino-3,5-difluorophenyl)-2-(butyl amino)ethan-1-ol

and pharmaceutically acceptable salts thereof.

Certain compounds of formula I that may be mentioned include:

-   2-(Butylamino)-1-(4-fluorophenyl)ethan-1-ol-   2-(Butylamino)-1-(4-fluorophenyl)ethan-1-ol-   2-(Butylamino)-1-(3-fluorophenyl)ethan-1-ol-   2-(tert-Butylamino)-1-(3-fluorophenyl)ethan-1-ol-   1-(4-Fluorophenyl)-2-((pentan-2-yl)amino)ethan-1-ol

and pharmaceutically acceptable salts thereof.

Further compounds of formula I that may be mentioned include:

-   1-(3-Fluorophenyl)-2-((2-methylpentan-2-yl)amino)ethan-1-ol-   2-(tert-Butylamino)-1-(2,3-difluorophenyl)ethan-1-ol-   2-(Butylamino)-1-(2,3-difluorophenyl)ethan-1-ol-   2-(tert-Butylamino)-1-(2-fluorophenyl)ethan-1-ol-   2-(Butylamino)-1-(2-fluorophenyl)ethan-1-ol-   2-(2-(tert-Butylamino)-1-hydroxyethyl)-5-fluorophenol-   2-(2-(Butylamino)-1-hydroxyethyl)-5-fluorophenol-   1-(3-fluorophenyl)-2-((1-methylcyclobutyl)amino)ethan-1-ol-   1-(3-fluorophenyl)-2-((1-methylcyclopropyl)amino)ethan-1-ol-   5-(2-(tert-Butylamino)-1-hydroxyethyl)-2-fluorophenol-   5-(2-(Butylamino)-1-hydroxyethyl)-2-fluorophenol-   3-(2-(tert-Butylamino)-1-hydroxyethyl)-2-fluorophenol-   3-(2-(Butylamino)-1-hydroxyethyl)-2-fluorophenol-   1-(3-Amino-2-fluorophenyl)-2-(tert-butylamino)ethan-1-ol-   1-(3-Amino-2-fluorophenyl)-2-(butylamino)ethan-1-ol-   1-(3-Fluorophenyl)-2-(neopentylamino)ethan-1-ol-   1-(3-fluorophenyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)ethan-1-ol-   1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-ol-   2-(tert-butylamino)-1-(3-fluoro-2-methylphenyl)ethan-1-ol

and pharmaceutically acceptable salts thereof.

As described herein, compounds of the first aspect of the invention mayalso contain one or more asymmetric carbon atoms and may thereforeexhibit optical and/or diastereoisomerism. Moreover, it has been foundthat certain such optical and/or diastereoisomers may show increasedutility in the treatment of hyperglycaemia or disorders characterized byhyperglycaemia (such as type 2 diabetes), as described herein.

In a particular embodiment of the first aspect of the invention, thecompound of formula I is such that the carbon substituted with theessential —OH group is in the (R) configuration, as understood by thoseskilled in the art.

Thus, in a particular embodiment, the compound of formula I is acompound of formula IB

wherein n, X, R¹, R² and R³ are as described herein (i.e. as describedin the first aspect of the invention, including all embodiments andparticular features, and combinations thereof).

In particular embodiments, there is provided a compound of formula IBwherein:

m represents 1;

n represents 0;

R¹ represents C₄₋₈ alkyl (e.g. C₄ alkyl, such as n-butyl); and/or (e.g.and)

R² and R³ both represent H.

In more particular embodiments, there is provided a compound of formulaIB wherein:

n represents 1 and the F atom is in the 4-position of the phenyl group;

R¹ represents C₄₋₈ alkyl (e.g. C₄ alkyl, such as n-butyl); and

R² and R³ both represent H.

In particular embodiments that may be mentioned, the essential —OH groupin compounds of formula I is in the (R) configuration.

In a yet more particular embodiment, the compound of formula I (or thecompound of formula IA or IB) is a compound of formula IC

wherein Y¹, Y², Y³, Y⁴, Y⁵, R¹, R² and R³ are as described herein (i.e.as described in the first aspect of the invention, including allembodiments and particular features, and combinations thereof).

For example, there is provided a compound of formula IC wherein:

Y¹, Y⁴ and Y⁵ each represent H;

one of Y² and Y³ represents F and the other represents H;

R¹ represents C₄₋₅ alkyl; and/or

R² and R³ both represent H.

As described herein, particular compounds of the first aspect of theinvention that may be mentioned include the compounds of the examplesprovided herein, and pharmaceutically acceptable salts thereof. Thus,compounds of formula IB or IC that may be mentioned include:

-   (R)-2-(Butylamino)-1-(4-fluorophenyl)ethan-1-ol-   (R)-2-(Butylamino)-1-(3-fluorophenyl)ethan-1-ol-   (R)-2-(tert-Butylamino)-1-(3-fluorophenyl)ethan-1-ol-   (R)-1-(4-fluorophenyl)-2-(((R)-pentan-2-yl)amino)ethan-1-ol-   (R)-1-(4-fluorophenyl)-2-(((S)-pentan-2-yl)amino)ethan-1-ol-   (R)-1-(3-fluorophenyl)-2-(((R)-pentan-2-yl)amino)ethan-1-ol-   (R)-1-(3-fluorophenyl)-2-(((S)-pentan-2-yl)amino)ethan-1-ol

and pharmaceutically acceptable salts thereof.

More particular compounds of formula I (e.g. compounds of formula IB orIC) include:

-   (R)-2-(Butylamino)-1-(4-fluorophenyl)ethan-1-ol-   (R)-2-(Butylamino)-1-(3-fluorophenyl)ethan-1-ol-   (R)-2-(tert-Butylamino)-1-(3-fluorophenyl)ethan-1-ol

and pharmaceutically acceptable salts thereof.

Certain particular compounds of formula I include:

-   (R)-1-(4-fluorophenyl)-2-(((R)-pentan-2-yl)amino)ethan-1-ol-   (R)-1-(4-fluorophenyl)-2-(((S)-pentan-2-yl)amino)ethan-1-ol-   (R)-1-(3-fluorophenyl)-2-(((R)-pentan-2-yl)amino)ethan-1-ol-   (R)-1-(3-fluorophenyl)-2-(((S)-pentan-2-yl)amino)ethan-1-ol

and pharmaceutically acceptable salts thereof.

Further compounds of formula I (e.g. compounds of formula IB or IC) thatmay be mentioned include:

-   (R)-1-(3-Fluorophenyl)-2-((2-methylpentan-2-yl)amino)ethan-1-ol-   (R)-2-(tert-Butylamino)-1-(2,3-difluorophenyl)ethan-1-ol-   (R)-2-(Butylamino)-1-(2,3-difluorophenyl)ethan-1-ol-   (R)-2-(tert-Butylamino)-1-(2-fluorophenyl)ethan-1-ol-   (R)-2-(Butylamino)-1-(2-fluorophenyl)ethan-1-ol-   (R)-2-(2-(tert-Butylamino)-1-hydroxyethyl)-5-fluorophenol-   (R)-2-(2-(Butylamino)-1-hydroxyethyl)-5-fluorophenol-   (R)-1-(3-fluorophenyl)-2-((1-methylcyclobutyl)amino)ethan-1-ol-   (R)-1-(3-fluorophenyl)-2-((1-methylcyclopropyl)amino)ethan-1-ol-   (R)-5-(2-(tert-Butylamino)-1-hydroxyethyl)-2-fluorophenol-   (R)-5-(2-(Butylamino)-1-hydroxyethyl)-2-fluorophenol-   (R)-3-(2-(tert-Butylamino)-1-hydroxyethyl)-2-fluorophenol-   (R)-3-(2-(Butylamino)-1-hydroxyethyl)-2-fluorophenol-   (R)-1-(3-Amino-2-fluorophenyl)-2-(tert-butylamino)ethan-1-ol-   (R)-1-(3-Amino-2-fluorophenyl)-2-(butylamino)ethan-1-ol-   (R)-1-(3-Fluorophenyl)-2-(neopentylamino)ethan-1-ol-   (R)-1-(3-fluorophenyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)ethan-1-ol-   (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-ol-   (R)-2-(tert-butylamino)-1-(3-fluoro-2-methylphenyl)ethan-1-ol

and pharmaceutically acceptable salts thereof.

In certain embodiments that may be mentioned, the compound of theinvention is not a compound selected from the list consisting of:

-   (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol; and-   (R)-1-(4-fluorophenyl)-2-((-pentan-2-yl)amino)ethan-1-ol.

In further embodiments that may be mentioned, the compound of theinvention is not a compound selected from the list consisting of:

-   (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol; and-   (R)-1-(4-fluorophenyl)-2-((-pentan-2-yl)amino)ethan-1-ol,

and pharmaceutically acceptable salts thereof.

The skilled person will understand that references to a specificsteroisomer of a compound of formula I (e.g. in the case of compounds offormula I, where the carbon substituted by the essential —OH group is inthe (R) configuration, as represented by compounds of formula IB andformula IC) will refer to the specific stereoisomer being present in thesubstantial absence of the corresponding opposite stereoisomer (e.g. inthe case of compounds of formula I, where the carbon substituted by theessential —OH group is in the (S) configuration).

For example, references to a compound of formula IC being present in thesubstantial absence of the corresponding opposite steroisomer (i.e. inthe (S) configuration) will refer to the substantial absence of thecorresponding compound as depicted below.

As used herein, references to the substantial absence of the otherstereoisomers (e.g. the corresponding opposite stereoisomer) will referto the desired stereoisomer (e.g. in the case of compounds of formula I,where the carbon substituted by the essential —OH group is in the (R)configuration) being present at a purity of at least 80% (e.g. at least90%, such as at least 95%) relative to the other stereoisomers (e.g. inthe case of compounds of formula I, where the carbon substituted by theessential —OH group is in the (S) configuration). Alternatively, in suchinstances, compounds may be indicated to be present in the substantialabsence of the compound in the other configuration (i.e. (S)configuration), which may indicate that the compound in the relevantconfiguration is present in an enantiomeric excess (e.e.) ordiastereomeric excess (d.e.), as appropriate, of at least 90% (such asat least 95%, at least 98% or, particularly, at least 99%, for exampleat least 99.9%).

For the avoidance of doubt, compounds referred to as having a specificstereochemistry at a defined position (e.g. in the case of compounds offormula I, the carbon substituted by the essential —OH group being inthe (R) configuration) may also have stereochemistry at one or moreother positions, and so may exist as mixtures of enantiomers ordiastereoisomers in relation to the stereochemistry at those positions.

Medical Uses

As indicated herein, the compounds of the invention, and thereforecompositions and kits comprising the same, are useful aspharmaceuticals.

Thus, according to a second aspect of the invention there is provided acompound of the first aspect of the invention, as hereinbefore defined(i.e. a compound as defined in the first aspect of the invention,including all embodiments and particular features thereof), for use as apharmaceutical (or for use in medicine).

For the avoidance of doubt, references to compounds as defined in thefirst aspect of the invention will include references to compounds offormula I (including all embodiments thereof) and pharmaceuticallyacceptable salts thereof.

As indicated herein, the compounds of the invention may be of particularuse in treating hyperglycaemia or a disorder characterized byhyperglycaemia.

Thus, in a third aspect of the invention, there is provided a compoundof the first aspect of the invention, as hereinbefore defined, for usein the treatment of hyperglycaemia or a disorder characterized byhyperglycaemia.

In an alternative third aspect of the invention, there is provided theuse of a compound of formula I, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofhyperglycaemia or a disorder characterized by hyperglycaemia.

In a further alternative third aspect of the invention, there isprovided a method of treating hyperglycaemia or a disorder characterizedby hyperglycaemia comprising administering to a patient in need thereofa therapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

For the avoidance of doubt, the term “hyperglycaemia” as used hereinwill be understood by those skilled in the art to refer to a conditionwherein an excessive amount of glucose circulates in blood plasma of thesubject experiencing the same. In particular, it may refer to a subject(e.g a human subject) having blood glucose levels higher than about 10.0mmol/L (such as higher than about 11.1 mmol/L, e.g. higher than about 15mmol/L), although it may also refer to a subject (e.g a human subject)having blood glucose levels higher than about 7 mmol/L for an extendedperiod of time (e.g. for greater than 24 hours, such as for greater than48 hours).

The skilled person will understand that references to the treatment of aparticular condition (or, similarly, to treating that condition) taketheir normal meanings in the field of medicine. In particular, the termsmay refer to achieving a reduction in the severity of one or moreclinical symptom associated with the condition. For example, in the caseof type 2 diabetes, the term may refer to achieving a reduction of bloodglucose levels. In particular embodiments, in the case of treatinghyperglycaemia or conditions characterised by hyperglycaemia, the termmay refer to achieving a reduction of blood glucose levels (for example,to or below about 10.0 mmol/mL (e.g. to levels in the range of fromabout 4.0 mmol/L to about 10.0 mmol/L), such as to or below about 7.5mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L to about7.5 mmol/L) or to or below about 6 mmol/mL (e.g. to levels in the rangeof from about 4.0 mmol/L to about 6.0 mmol/L)).

As used herein, references to patients will refer to a living subjectbeing treated, including mammalian (e.g. human) patients. Thus, inparticular embodiments of the first aspect of the invention, thetreatment is in a mammal (e.g. a human).

As used herein, the term therapeutically effective amount will refer toan amount of a compound that confers a therapeutic effect on the treatedpatient. The effect may be objective (i.e. measurable by some test ormarker) or subjective (i.e. the subject gives an indication of and/orfeels an effect).

Although compounds of the first aspect of the invention may possesspharmacological activity as such, certain pharmaceutically-acceptable(e.g. “protected”) derivatives of compounds of the invention may existor be prepared which may not possess such activity, but may beadministered parenterally or orally and thereafter be metabolised in thebody to form compounds of the invention. Such compounds (which maypossess some pharmacological activity, provided that such activity isappreciably lower than that of the active compounds to which they aremetabolised) may therefore be described as “prodrugs” of compounds ofthe invention.

As used herein, references to prodrugs will include compounds that forma compound of the invention, in an experimentally-detectable amount,within a predetermined time, following enteral or parenteraladministration (e.g. oral or parenteral administration). All prodrugs ofthe compounds of the first aspect of the invention are included withinthe scope of the invention.

For the avoidance of doubt, the compounds of the first aspect of theinvention are useful because they possess pharmacological activity,and/or are metabolised in the body following oral or parenteraladministration to form compounds that possess pharmacological activity.In particular, as described herein, compounds of the first aspect of theinvention are useful in the treatment of hyperglycaemia or disorderscharacterized by hyperglycaemia (such as type 2 diabetes), which termswill be readily understood by one of skill in the art (as describedherein).

In a particular embodiment, the treatment is of a disorder (which mayalso be referred to as a condition or disease) characterised byhyperglycaemia.

In particular embodiments, compounds of the invention (i.e. compounds offormula I, including all embodiments thereof) are for use in thetreatment of type 2 diabetes (or useful in the manufacture of amedicament for such treatment, or useful in a method for such treatment,as described herein).

In particular embodiments of the first aspect of the invention, thedisorder is type 2 diabetes, such as type 2 diabetes of a sub-typeselected from the list consisting of maturity-onset diabetes in theyoung (MODY), ketosis-prone diabetes in adults, latent autoimmunediabetes of adults (LADA), and gestational diabetes.

In further particular embodiments, the treatment of type 2 diabetes isin a non-obese patient.

For the avoidance of doubt, the skilled person will understand thatpatients with a Body Mass Index (BMI) of greater than 30 are consideredto be obese.

In particular embodiments, the treatment may be of hyperglycaemia in apatient who is at risk of developing type 2 diabetes, which conditionmay be defined as pre-diabetes. Thus, compounds of the invention may beuseful in the prevention of type 2 diabetes (e.g. in a patient havingpre-diabetes).

As used herein, the term prevention (and, similarly, preventing)includes references to the prophylaxis of the disease or disorder (andvice-versa). As such, references to prevention may also be references toprophylaxis, and vice versa. In particular, the term may refer toachieving a reduction in the likelihood of the patient (or healthysubject) developing the condition (for example, at least a 10%reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a50% reduction).

In more particular embodiments, the type 2 diabetes is characterised bythe patient displaying severe insulin resistance (SIR).

In further embodiments, the treatment may be of hyperglycaemia in apatient having type 1 diabetes. Thus, compounds of the invention may beuseful in the treatment of hyperglycaemia in type 1 diabetes.

The skilled person will understand that compounds of the invention maybe useful in treating hyperglycaemia in patients having impaired insulinproduction, such as in patients having cystic fibrosis. Thus, in furtherembodiments, the disorder characterized by hyperglycaemia is cysticfibrosis-related diabetes.

In particular embodiments that may be mentioned, the disordercharacterised by hyperglycaemia is (or is characterized by) severeinsulin resistance (SIR), which may be understood by those in the art torefer to disorders wherein typically the subject has normal, or in somecases increased, insulin production but significantly reduced insulinsensitivity. In particular instances, such patients may be non-obese(e.g. being of a healthy weight). Thus, in particular embodiments, suchtreatments are performed in patients who are not defined as being obese(e.g. in patients who are defined as being of a healthy weight).

For example, SIR may be identified in a patient based in said patienthaving fasting insulin >150 pmol/L and/or a peak insulin on glucosetolerance testing of >1,500 pmol/L, particularly in individuals with aBMI <30 kg/m² (which patient may otherwise have normal glucosetolerance).

More particularly, SIR may be characterised by the patient having nosignificant response to the presence of insulin, which may result from adefect (e.g. a genetic defect) in the function of the insulin receptor.

Particular disorders that may be characterised by SIR include:Rabson-Mendenhall syndrome, Donohue's syndrome (leprechaunism), Type Aand Type B syndromes of insulin resistance, the HAIR-AN(hyperandrogenism, insulin resistance, and acanthosis nigricans)syndromes, pseudoacromegaly, and lipodystrophy.

More particular disorders that may be characterised by SIR includeDonohue's syndrome and Type A syndrome of insulin resistance and, yetmore particularly, Rabson-Mendenhall syndrome.

The skilled person will understand that treatment with compounds of thefirst aspect of the invention may further comprise (i.e. be combinedwith) further (i.e. additional/other) treatment(s) for the samecondition. In particular, treatment with compounds of the invention maybe combined with other means for the treatment of type 2 diabetes, suchas treatment with one or more other therapeutic agent that is useful inthe treatment of type 2 diabetes as known to those skilled in the art,such as therapies comprising requiring the patient to undergo a changeof diet and/or undertake exercise regiments, and/or surgical proceduresdesigned to promote weight loss (such as gastric band surgery).

In particular, treatment with compounds of the invention may beperformed in combination with (e.g. in a patient who is also beingtreated with) one or more (e.g. one) additional compounds (i.e.therapeutic agents) that:

(i) are capable of reducing blood sugar levels; and/or

(ii) are insulin sensitizers; and/or

(iii) enhance insulin release,

all of which are described herein below.

In alternative embodiments, compounds of the first aspect of theinvention (i.e. compounds of the invention) may be useful in thetreatment of a non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) is defined by excessive fataccumulation in the form of triglycerides (steatosis) in the liver(designated as an accumulation of greater than 5% of hepatocyteshistologically). It is the most common liver disorder in developedcountries (for example, affecting around 30% of US adults) and mostpatients are asymptomatic. If left untreated, the condition mayprogressively worsen and may ultimately lead to cirrhosis of the liver.NAFLD is particularly prevalent in obese patients, with around 80%thought to have the disease.

A sub-group of NAFLD patients (for example, between 2 and 5% of USadults) exhibit liver cell injury and inflammation in addition toexcessive fat accumulation. This condition, designated as non-alcoholicsteatohepatitis (NASH), is virtually indistinguishable histologicallyfrom alcoholic steatohepatitis. While the simple steatosis seen in NAFLDdoes not directly correlate with increased short-term morbidity ormortality, progression of this condition to NASH dramatically increasesthe risks of cirrhosis, liver failure and hepatocellular carcinoma.Indeed, NASH is now considered to be one of the main causes of cirrhosis(including cryptogenic cirrhosis) in the developed world.

The exact cause of NASH has yet to be elucidated, and it is almostcertainly not the same in every patient. It is most closely related toinsulin resistance, obesity, and the metabolic syndrome (which includesdiseases related to diabetes mellitus type 2, insulin resistance,central (truncal) obesity, hyperlipidaemia, low high-density lipoprotein(HDL) cholesterol, hypertriglyceridemia, and hypertension). However, notall patients with these conditions have NASH, and not all patients withNASH suffer from one of these conditions. Nevertheless, given that NASHis a potentially fatal condition, leading to cirrhosis, liver failureand hepatocellular carcinoma, there exists a clear need for an effectivetreatment.

In particular embodiments, compounds of the invention (i.e. compounds offormula I, including all embodiments thereof) are for use in thetreatment of a non-alcoholic fatty liver disease (or useful in themanufacture of a medicament for such treatment, or useful in a methodfor such treatment, as described herein).

The process by which the triglyceride fat accumulates in liver cells iscalled steatosis (i.e. hepatic steatosis). The skilled person willunderstand that the term “steatosis” encompasses the abnormal retentionof fat (i.e. lipids) within a cell. Thus, in particular embodiments ofthe first aspect of the invention, the treatment or prevention is of afatty liver disease which is characterized by steatosis.

During steatosis, excess lipids accumulate in vesicles that displace thecytoplasm of the cell. Over time, the vesicles can grow large enough todistort the nucleus, and the condition is known as macrovesicularsteatosis. Otherwise, the condition may be referred to as microvesicularsteatosis. Steatosis is largely harmless in mild cases; however, largeaccumulations of fat in the liver can cause significant health issues.Risk factors associated with steatosis include diabetes mellitus,protein malnutrition, hypertension, obesity, anoxia, sleep apnea and thepresence of toxins within the cell.

As described herein, fatty liver disease is most commonly associatedwith alcohol or a metabolic syndrome (for example, diabetes,hypertension, obesity or dyslipidemia). Therefore, depending on theunderlying cause, fatty liver disease may be diagnosed asalcohol-related fatty liver disease or non-alcoholic fatty liver disease(NAFLD).

Particular diseases or conditions that are associated with fatty liverdisease that are not related to alcohol include metabolic conditionssuch as diabetes, hypertension, obesity, dyslipidemia,abetalipoproteinemia, glycogen storage diseases, Weber-Christiandisease, acute fatty liver of pregnancy, and lipodystrophy. Othernon-alcohol related factors related to fatty liver diseases includemalnutrition, total parenteral nutrition, severe weight loss, refeedingsyndrome, jejunoileal bypass, gastric bypass, polycystic ovary syndromeand diverticulosis.

The compounds of the invention have been found to be particularly usefulin the treatment or prevention of NAFLD, which may be referred to as afatty liver disease which is not alcohol related. A fatty liver diseasewhich is “not alcohol related” may be diagnosed wherein alcoholconsumption of the patient is not considered to be a main causativefactor. A typical threshold for diagnosing a fatty liver disease as “notalcohol related” is a daily consumption of less than 20 g for femalesubjects and less than 30 g for male subjects.

If left untreated, subjects suffering from fatty liver disease may beginto experience inflammation of the liver (hepatitis). It has beenpostulated that one of the possible causes of this inflammation may belipid peroxidative damage to the membranes of the liver cells.Inflammation of a fatty liver can lead to a number of serious conditionsand it is therefore desirable to treat or prevent fatty liver diseasebefore inflammation occurs. Thus, in particular embodiments of the firstaspect of the invention, the treatment or prevention is of a NAFLD whichis associated with inflammation.

Non-alcoholic steatohepatitis (NASH) is the most aggressive form ofNAFLD, and is a condition in which excessive fat accumulation(steatosis) is accompanied by inflammation of the liver. If advanced,NASH can lead to the development of scar tissue in the liver (fibrosis)and, eventually, cirrhosis. As described above, the compounds of theinvention have been found to be useful in the treatment or prevention ofNAFLD, particularly when accompanied by inflammation of the liver. Itfollows that the compounds of the invention are also useful in thetreatment or prevention of NASH. Therefore, in a further embodiment ofthe first aspect of the invention, the treatment or prevention is ofnon-alcoholic steatohepatitis (NASH).

The skilled person will understand that treatment with compounds of thefirst aspect of the invention may further comprise (i.e. be combinedwith) further (i.e. additional/other) treatment(s) for the samecondition. In particular, treatment with compounds of the invention maybe combined with other means for the treatment of a fatty liver disease,as described herein, such as treatment with one or more othertherapeutic agent that is useful in the treatment of a fatty liverdisease as known to those skilled in the art; for example, therapiescomprising requiring the patient to undergo a change of diet and/orundertake exercise regiments, and/or surgical procedures designed topromote weight loss (such as gastric band surgery).

In particular, treatment with compounds of the invention may beperformed in combination with (e.g. in a patient who is also beingtreated with) one or more (e.g. one) additional compounds (i.e.therapeutic agents) that are capable of reducing the level of fat (e.g.triglycerides) in the liver.

References to treatment of a fatty liver disease may refer to achievinga therapeutically significant reduction of fat (e.g. triglycerideslevels) in liver cells (such as a reduction of at least 5% by weight,e.g. a reduction of at least 10%, or at least 20% or even 25%).

Pharmaceutical Compositions

As described herein, compounds of the first aspect of the invention(i.e. compounds of the invention) are useful as pharmaceuticals. Suchcompounds may be administered alone or may be administered by way ofknown pharmaceutical compositions/formulations.

In a fourth aspect of the invention, there is provided a pharmaceuticalcomposition comprising a compound as defined in the second or thirdaspect of the invention, and optionally one or more pharmaceuticallyacceptable adjuvant, diluent and/or carrier.

The skilled person will understand that references herein to compoundsof the first aspect of the invention being for particular uses (and,similarly, to uses and methods of use relating to compounds of theinvention) may also apply to pharmaceutical compositions comprisingcompounds of the invention as described herein.

In a fifth aspect of the invention, there is provided a pharmaceuticalcomposition for use in the treatment of hyperglycaemia or a disordercharacterized by hyperglycaemia (as defined herein, such as type 2diabetes) comprising a compound as defined in the first aspect of theinvention, and optionally one or more pharmaceutically acceptableadjuvant, diluent and/or carrier.

In an alternative fifth aspect of the invention, there is provided apharmaceutical composition for use in the treatment or prevention of anon-alcoholic fatty liver disease, as defined herein.

The skilled person will understand that compounds of the first aspect ofthe invention may act systemically and/or locally (i.e. at a particularsite).

The skilled person will understand that compounds and compositions asdescribed in the first to fifth aspects of the invention will normallybe administered orally, intravenously, subcutaneously, buccally,rectally, dermally, nasally, tracheally, bronchially, sublingually,intranasally, topically, by any other parenteral route or viainhalation, in a pharmaceutically acceptable dosage form. Pharmaceuticalcompositions as described herein will include compositions in the formof tablets, capsules or elixirs for oral administration, suppositoriesfor rectal administration, sterile solutions or suspensions forparenteral or intramuscular administration, and the like. Alternatively,particularly where such compounds of the invention act locally,pharmaceutical compositions may be formulated for topicaladministration.

Thus, in particular embodiments of the fourth and fifth aspects of theinvention, the pharmaceutical formulation is provided in apharmaceutically acceptable dosage form, including tablets or capsules,liquid forms to be taken orally or by injection, suppositories, creams,gels, foams, inhalants (e.g. to be applied intranasally), or formssuitable for topical administration. For the avoidance of doubt, in suchembodiments, compounds of the invention may be present as a solid (e.g.a solid dispersion), liquid (e.g. in solution) or in other forms, suchas in the form of micelles.

For example, in the preparation of pharmaceutical formulations for oraladministration, the compound may be mixed with solid, powderedingredients such as lactose, saccharose, sorbitol, mannitol, starch,amylopectin, cellulose derivatives, gelatin, or another suitableingredient, as well as with disintegrating agents and lubricating agentssuch as magnesium stearate, calcium stearate, sodium stearyl fumarateand polyethylene glycol waxes. The mixture may then be processed intogranules or compressed into tablets.

Soft gelatin capsules may be prepared with capsules containing one ormore active compounds (e.g. compounds of the first and, therefore,second and third aspects of the invention, and optionally additionaltherapeutic agents), together with, for example, vegetable oil, fat, orother suitable vehicle for soft gelatin capsules. Similarly, hardgelatine capsules may contain such compound(s) in combination with solidpowdered ingredients such as lactose, saccharose, sorbitol, mannitol,potato starch, corn starch, amylopectin, cellulose derivatives orgelatin.

Dosage units for rectal administration may be prepared (i) in the formof suppositories which contain the compound(s) mixed with a neutral fatbase; (ii) in the form of a gelatin rectal capsule which contains theactive substance in a mixture with a vegetable oil, paraffin oil, orother suitable vehicle for gelatin rectal capsules; (iii) in the form ofa ready-made micro enema; or (iv) in the form of a dry micro enemaformulation to be reconstituted in a suitable solvent just prior toadministration.

Liquid preparations for oral administration may be prepared in the formof syrups or suspensions, e.g. solutions or suspensions, containing thecompound(s) and the remainder of the formulation consisting of sugar orsugar alcohols, and a mixture of ethanol, water, glycerol, propyleneglycol and polyethylene glycol. If desired, such liquid preparations maycontain colouring agents, flavouring agents, saccharine andcarboxymethyl cellulose or other thickening agent. Liquid preparationsfor oral administration may also be prepared in the form of a dry powderto be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution ofthe compound(s) in a pharmaceutically acceptable solvent. Thesesolutions may also contain stabilizing ingredients and/or bufferingingredients and are dispensed into unit doses in the form of ampoules orvials. Solutions for parenteral administration may also be prepared as adry preparation to be reconstituted with a suitable solventextemporaneously before use.

The skilled person will understand that compounds of the invention, andpharmaceutically-acceptable salts thereof, may be administered (forexample, as formulations as described hereinabove) at varying doses,with suitable doses being readily determined by one of skill in the art.Oral, pulmonary and topical dosages (and subcutaneous dosages, althoughthese dosages may be relatively lower) may range from between about 0.01μg/kg of body weight per day (μg/kg/day) to about 200 μg/kg/day,preferably about 0.01 to about 10 μg/kg/day, and more preferably about0.1 to about 5.0 μg/kg/day. For example, when administered orally,treatment with such compounds may comprise administration of aformulations typically containing between about 0.01 μg to about 2000mg, for example between about 0.1 μg to about 500 mg, or between 1 μg toabout 100 mg (e.g. about 20 μg to about 80 mg), of the activeingredient(s). When administered intravenously, the most preferred doseswill range from about 0.001 to about 10 μg/kg/hour during constant rateinfusion. Advantageously, treatment may comprise administration of suchcompounds and compositions in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily (e.g. twice daily with reference to the doses described herein,such as a dose of 10 mg, 20 mg, 30 mg or 40 mg twice daily, or 10 μg, 20μg, 30 μg or 40 μg twice daily).

In any event, the skilled person (e.g. the physician) will be able todetermine the actual dosage which will be most suitable for anindividual patient, which is likely to vary with the route ofadministration, the type and severity of the condition that is to betreated, as well as the species, age, weight, sex, renal function,hepatic function and response of the particular patient to be treated.The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

As described herein above, the skilled person will understand thattreatment with compounds of the first aspect of the invention mayfurther comprise (i.e. be combined with) further (i.e. additional/other)treatment(s) for the same condition. In particular, treatment withcompounds of the invention may be combined with other means for thetreatment of hyperglycaemia or a disorder characterized byhyperglycaemia (as defined herein, such as type 2 diabetes), such astreatment with one or more other therapeutic agent that is useful in thetreatment of hyperglycaemia or a disorder characterized byhyperglycaemia (as defined herein, such as type 2 diabetes).

In particular embodiments of the fourth and fifth aspects of theinvention, the pharmaceutical composition may further comprise one ormore additional (i.e. other) therapeutic agent.

In more particular embodiments, the one or more additional therapeuticagent is an agent for the treatment of type 2 diabetes as known to thoseskilled in the art, such as metformin, sulfonylureas (e.g. carbutamide,acetohexamide, chlorpropamide, tolbutamide. glipizide (glucotrol),gliclazide, glibenclamide, glyburide (Micronase), glibornuride,gliquidone, glisoxepide, glyclopyramide, glimepiride (Amaryl),glimiprime, JB253 or JB558), thiazolidinediones (e.g. pioglitazone,rosiglitazone (Avandia), lobeglitazone (Duvie) and troglitazone(Rezulin)), dipeptidyl peptidase-4 inhibitors (e.g. sitagliptin,vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin,alogliptin, trelagliptin, gemigliptin, dutogliptin and omarigliptin),SGLT2 inhibitors (e.g. dapagliflozin, empagliflozin, canagliflozin,ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate, and ertugliflozin), and glucagon-like peptide-1 (GLP-1)analogues.

The skilled person will understand that combinations of therapeuticagents may also described as a combination product and/or provided as akit-of-parts.

In a sixth aspect of the invention, there is provided a combinationproduct comprising:

(A) a compound as defined in the first aspect of the invention; and

(B) one or more additional therapeutic agent,

wherein each of components (A) and (B) is formulated in admixture,optionally with one or more a pharmaceutically-acceptable adjuvant,diluent or carrier.

In a seventh aspect of the invention, there is provided a kit-of-partscomprising:

(a) a compound as defined in the first aspect of the invention, (or apharmaceutical composition comprising the same) or a pharmaceuticalcomposition as defined in the fourth or fifth aspect of the invention;and

(b) one or more other therapeutic agent, optionally in admixture withone or more pharmaceutically-acceptable adjuvant, diluent or carrier,

which components (a) and (b) are each provided in a form that issuitable for administration in conjunction with the other.

In particular embodiments (e.g. of the sixth and seventh aspects of theinvention), the additional therapeutic agent is a therapeutic agent thatis useful for the treatment of hyperglycaemia or a disordercharacterized by hyperglycaemia (e.g. type 2 diabetes), as known tothose skilled in the art (such as those described herein).

For example, in particular embodiments of the fourth to seventh aspectsof the invention, the additional therapeutic agent is an agent that:

(i) is capable of reducing blood sugar levels; and/or

(ii) is an insulin sensitizer; and/or

(iii) is able to enhance insulin release,

which agents will be readily identified by those skilled in the art andinclude, in particular, such therapeutic agents that are commerciallyavailable (e.g. agents that the subject of a marketing authorization inone or more territory, such as a European or US marketingauthorization).

The skilled person will understand that references to therapeutic agentscapable of reducing blood glucose levels may refer to compounds capableof reducing levels of blood by at least 10% (such as at least 20%, atleast 30% or at least 40%, for example at least 50%, at least 60%, atleast 70% or at least 80%, e.g. at least 90%) when compared to the bloodglucose levels prior to treatment with the relevant compound.

In alternative embodiments of the sixth and seventh aspects of theinvention, the additional therapeutic agent is an agent for thetreatment or prevention of a non-alcoholic fatty liver disease (such asNASH), which agents will be readily identified by those skilled in theart and include, in particular, such therapeutic agents that arecommercially available (e.g. agents that the subject of a marketingauthorization in one or more territory, such as a European or USmarketing authorization).

Preparation of Compounds/Compositions

Pharmaceutical compositions/formulations, combination products and kitsas described herein may be prepared in accordance with standard and/oraccepted pharmaceutical practice.

Thus, in a further aspect of the invention there is provided a processfor the preparation of a pharmaceutical composition/formulation, ashereinbefore defined, which process comprises bringing into associationa compound of the invention, as hereinbefore defined, with one or morepharmaceutically-acceptable adjuvant, diluent or carrier.

In further aspects of the invention, there is provided a process for thepreparation of a combination product or kit-of-parts as hereinbeforedefined, which process comprises bringing into association a compound ofthe invention, as hereinbefore defined, or a pharmaceutically acceptablesalt thereof with the other therapeutic agent that is useful in thetreatment of hyperglycaemia or a disorder characterized byhyperglycaemia (e.g. type 2 diabetes), and at least onepharmaceutically-acceptable adjuvant, diluent or carrier.

As used herein, references to bringing into association will mean thatthe two components are rendered suitable for administration inconjunction with each other.

Thus, in relation to the process for the preparation of a kit of partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit of parts may be:

(i) provided as separate formulations (i.e. independently of oneanother), which are subsequently brought together for use in conjunctionwith each other in combination therapy; or

(ii) packaged and presented together as separate components of a“combination pack” for use in conjunction with each other in combinationtherapy.

Compounds as defined in the first aspect of the invention (i.e.compounds of the invention) may be prepared in accordance withtechniques that are well known to those skilled in the art, such asthose described in the examples provided hereinafter.

For example, there is provided a process for the preparation of acompound of formula I, or a pharmaceutically acceptable salt thereof, asdefined in the first aspect of the invention (which may be utilised inthe preparation of, for example, a compound as defined in the secondaspect of the invention), which process comprises:

(i) reaction of a compound of formula II

wherein X¹, X², X³, X⁴, R² and R³ are as defined hereinabove, with acompound of formulaH₂N—R¹  (III)

wherein R¹ is as defined hereinabove, optionally in the presence of asuitable solvent known to those skilled in the art;

(iia) reaction of a compound of formula IV

wherein m, n, X, R¹, R² and R³ are as defined hereinabove and Y¹represents H or PG¹ wherein PG¹ is a suitable protecting group as knownto those skilled in the art (e.g. —C(O)OtBu or —SO₂CH₃) with a suitablereduction agent as known to those skilled in the art (such as NaBH₄ orLiAlH₄, or a suitable chiral reducing agent), or by hydrogenation in thepresence of a suitable catalyst (such as a chiral catalyst or additive);

(iib) for compounds of formula IB (and, similarly, compounds of formulaIC) reaction of a compound of formula IV as defined herein above butwherein Y¹ represents PG¹ wherein PG¹ is a suitable protecting group asknown to those skilled in the art (e.g. —C(O)OtBu) in the presence of asuitable catalyst (such as a complex between (1S,2S)-(+)-N-(4-toluenesulphonyl)-1,2-diphenylethylene diamine and[Ru(cymene)Cl₂]₂)) in the presence of hydrogen or a suitable hydrogendonor (such as formic acid) and optionally in the presence of a base(e.g. Et₃N) and in the presence of a suitable solvent (such as CH₂Cl₂);

(iii) for compounds wherein at least one X is present and represents—OH, deprotection of a compound of formula V

wherein m, n, R¹, R² and R³ are as defined hereinabove, Y² represents Hor PG², wherein PG² represents a suitable protecting group as known tothose skilled in the art, and PG³ represents a suitable protecting groupas known to those skilled in the art (e.g. benzyl or alkyl, such asmethyl) under conditions known to those skilled in the art (for example:in the case of benzyl, in the presence of hydrogen and a suitablecatalyst or a suitable acid; in the case of alkyl, such as methyl, inthe presence of BBr₃, HBr or alkyl sulfides);

(iv) for compounds wherein at least one X is present and represents NH₂or NHC(O)CH₃, deprotection of a compound of formula VI

wherein m, n, X, R¹, R² and R³ are as defined hereinabove, Y³ representsH or PG⁵, wherein PG⁵ represents a suitable protecting group as known tothose skilled in the art, Y⁴ represents H, C(O)CH₃ or PG⁶, wherein PG⁶represents a suitable protecting group as known to those skilled in theart, and PG⁴ represents a suitable protecting group as known to thoseskilled in the art (e.g. carbamate protecting groups (such astert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc) andcarboxybenzyl (Cbz) and amide protecting groups (such as acetyl andbenzoyl)) under conditions known to those skilled in the art (forexample in the case of Boc, in the presence of a suitable acid (e.g.trifluoroacetic acid or HCl). PG⁴, PG⁵ (if present) and PG⁶ (if present)may each represent the same protecting group, and therefore may bedeprotected under a single set of conditions;

(v) for compounds wherein at least one X is present and represents NH₂,reduction of a compound of formula VII

wherein m, n, X, R¹, R² and R³ are as defined hereinabove, underconditions known to those skilled in the art (for example, byhydrogenation, such as hydrogenation using hydrogen gas and a suitablecatalyst as known to those skilled in the art, (e.g. Pd—C, PtO₂,Raney-Nickel), Fe or Zn in acidic media (e.g. AcOH), borohydridestogether with a suitable catalyst (e.g. NaBH₄ and Raney-Nickel), oragents such as SnC₂, TiCl₃, Sml₂, and the like. Those skilled in the artwill understand that certain functional groups, such as the essential—OH and/or the —NHR¹ groups) may need to be protected (and deprotected)one or more times during the reaction, which protections (anddeprotections) may be performed using techniques known to those skilledin the art.

Compounds of formulae II, III, IV, V VI and VII are either commerciallyavailable, are known in the literature, or may be obtained either byanalogy with the processes described herein, or by conventionalsynthetic procedures, in accordance with standard techniques, fromavailable starting materials (e.g. appropriately substitutedbenzaldehydes, styrenes or phenacyl bromides (or phenacylchloride, andthe like) using appropriate reagents and reaction conditions. In thisrespect, the skilled person may refer to inter alia “ComprehensiveOrganic Synthesis” by B. M. Trost and I. Fleming, Pergamon Press, 1991.Further references that may be employed include “Science of Synthesis”,Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag,2006.

The substituents X, R¹, R² and R³, as hereinbefore defined, may bemodified one or more times, after or during the processes describedabove for preparation of compounds of formula I by way of methods thatare well known to those skilled in the art. Examples of such methodsinclude substitutions, reductions, oxidations, dehydrogenations,alkylations, dealkylations, acylations, hydrolyses, esterifications,etherifications, halogenations and nitrations. The precursor groups canbe changed to a different such group, or to the groups defined informula I, at any time during the reaction sequence. The skilled personmay also refer to “Comprehensive Organic Functional GroupTransformations” by A. R. Katritzky, O. Meth-Cohn and C. W. Rees,Pergamon Press, 1995 and/or “Comprehensive Organic Transformations” byR. C. Larock, Wiley-VCH, 1999.

Such compounds may be isolated from their reaction mixtures and, ifnecessary, purified using conventional techniques as known to thoseskilled in the art. Thus, processes for preparation of compounds of theinvention as described herein may include, as a final step, isolationand optionally purification of the compound of the invention (e.g.isolation and optionally purification of the compound of formula I orIA).

The skilled person will understand that compounds of formula I havingspecific stereochemistry (such as compounds of formula IB and IC) may beprovided by reacting suitable starting materials having the requiredstereochemistry in processes as described herein.

For example, compounds of formula IB and IC may be provided by reactingcompounds having the required stereochemistry in processes as describedin step (i) or step (iii) in the processes described herein above.

Further, the skilled person will understand that suitable startingmaterials having the required stereochemistry (such as suitablecompounds of formula II and V wherein the carbon substituted with theessential oxygen is the (R) configuration, as required for thepreparation of compounds of formula IB and IC) may be prepared byanalogy with the process described in step (iib) herein above.

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be applied and removed in accordance withtechniques that are well known to those skilled in the art and asdescribed hereinafter. For example, protected compounds/intermediatesdescribed herein may be converted chemically to unprotected compoundsusing standard deprotection techniques. The type of chemistry involvedwill dictate the need, and type, of protecting groups as well as thesequence for accomplishing the synthesis. The use of protecting groupsis fully described in “Protective Groups in Organic Synthesis”, 3rdedition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999).

Compounds as described herein (in particular, compounds as defined inthe first and, therefore, second and third aspects of the invention) mayhave the advantage that they may be more efficacious than, be less toxicthan, be longer acting than, be more potent than, produce fewer sideeffects than, be more easily absorbed than, and/or have a betterpharmacokinetic profile (e.g. higher oral bioavailability and/or lowerclearance) than, and/or have other useful pharmacological, physical, orchemical properties over, compounds known in the prior art, whether foruse in the above-stated indications or otherwise. In particular, suchcompounds may have the advantage that they are more efficacious and/orexhibit advantageous properties in vivo.

Without wishing to be bound by theory, compounds as described herein arethought to be potent agonists of the β₂-adrenergic receptor, whichallows for increased glucose uptake in skeletal muscle cells.

In addition, compounds as described herein are thought to be agonists ofthe β₂-adrenergic receptor without (or with only a minimal effect in)inducing cAMP production. It is thought that this allows for theincreased glucose uptake in skeletal muscle cells with lower levels ofside effects than would result from other treatments. Further, combiningcompounds as described herein with therapeutic agents that are able todecrease blood glucose levels is thought to provide an effectivecombination therapy.

Furthermore, compounds of the invention may be particularly resistant tometabolism (e.g. first-past metabolism), i.e. the process by whichpharmaceutical agents are biotransformed to aid excretion.

EXAMPLES

The present invention is illustrated by way of the following examples.

Chemicals and reagents were obtained from commercial suppliers and wereused as received unless otherwise stated. All reactions involvingmoisture sensitive reagents were performed in oven or flame driedglassware under a positive pressure of nitrogen or argon.

Abbreviations

Abbreviations as used herein will be known to those skilled in the art.In particular, the following abbreviations may be used herein.

AcOH acetic acid

aq aqueous

atm atmosphere

Boc₂O di-tert-butyldicarbonate

DIPEA N,N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

eq equivalent

EtOAc ethyl acetate

HPLC high-performance liquid chromatography

iPrOH isopropanol

MeCN acetonitrile

MeOH methanol

Pd—C palladium on carbon

rt room temperature

sat saturated

TFA trifluoroacetic acid

THF tetrahydrofuran

Example Compounds

In the event that there is a discrepancy between nomenclature and thestructure of compounds as depicted graphically, it is the latter thatpresides (unless contradicted by any experimental details that may begiven and/or unless it is clear from the context).

Example 1: 2-(Butylamino)-1-(3,5-difluorophenyl)ethan-1-ol

(a) 2-(3,5-Difluorophenyl)oxirane

A solution of trimethylsulfonium iodide (413 mg, 2.02 mmol) in DMSO (6mL) was added dropwise to an ice-cooled suspension of NaH (2.1 mmol,prepared from 84 mg 60% NaH in mineral oil by washing with Et₂O) in THF(6 mL). The ice-cooled mixture was stirred for 30 min and a solution of3,5-difluorobenzaldehyde (250 mg, 1.76 mmol) in THF (2.45 mL) was slowlyadded. The mixture was stirred for 20 min, the cooling bath removed andstirring was continued at rt for 2 h. The mixture was poured onto iceand extracted with Et₂O. The combined extracts were washed with water,brine, dried (Na₂SO₄) and concentrated to give the sub-title compound(257 mg, 1.65 mmol, 94%) which was used in the next step without anyfurther purification.

(b) 2-(Butylamino)-1-(3,5-difluorophenyl)ethan-1-ol

A mixture of 2-(3,5-difluorophenyl)oxirane (100 mg, 0.64 mmol),n-butylamine (158 μL, 1.60 mmol) and MeOH (1 mL) was stirred at refluxfor 6 h. The mixture was concentrated and the residue purified bychromatography to give the title compound (98 mg, 0.43 mmol, 67%).

¹H NMR (300 MHz, CDCl₃): δ 6.97-6.84 (m, 2H), 6.69 (tt, J=8.8, 2.4 Hz,1H), 4.64 (dd, J=8.7, 3.6 Hz, 1H), 2.92 (dd, J=12.0, 3.6 Hz, 1H),2.72-2.55 (m, 3H), 1.52-1.27 (m, 4H), 0.92 (t, J=7.2 Hz, 3H).

Example 2: 2-(Butylamino)-1-(3,4-difluorophenyl)ethan-1-ol

(a) 2-(Benzyl(butyl)amino)-1-(3,4-difluorophenyl)ethan-1-ol

The sub-title compound was prepared in accordance with the procedure inExample 1, Steps (a) and (b) from 3,4-difluorobenzaldehyde andN-benzylbutylamine.

(b) 2-(Butylamino)-1-(3,4-difluorophenyl)ethan-1-ol

A mixture of 2-(benzyl(butyl)amino)-1-(3,4-difluorophenyl)ethan-1-ol (70mg, 0.22 mmol), 10% Pd—C(23.3 mg, 0.022 mmol) and AcOH (2 mL) washydrogenated at 6.5 atm at rt for 2 h, filtered through Celite andconcentrated. NaHCO₃ (aq, sat) was added to the residue, which wasextracted with Et₂O. The combined extracts were washed with water,brine, dried (Na₂SO₄), concentrated and purified by chromatography togive the title compound (30 mg, 0.13 mmol, 60%).

¹H NMR (400 MHz, CDCl₃): δ 7.24-7.19 (m, 1H), 7.15-7.04 (m, 2H), 4.67(dd, J=9.2, 3.5 Hz, 1H), 2.89 (dd, J=12.2, 3.6 Hz, 1H), 2.86-2.69 (br s,2H overlapping), 2.74-2.58 (m, 3H), 1.54-1.42 (m, 2H), 1.35 (h, J=7.2Hz, 2H), 0.92 (t, J=7.3 Hz, 3H)

Example 3: (R)-2-(Butylamino)-1-(4-fluorophenyl)ethan-1-ol

(a) tert-Butyl butyl(2-(4-fluorophenyl)-2-oxoethyl)carbamate

A solution of 4-fluorophenacyl bromide (300 mg, 1.38 mmol) in CH₂Cl₂ (4mL) was added over 10 min to a mixture of n-butylamine (205 μL, 2.07mmol), DIPEA (239 μL, 1.38 mmol) and CH₂Cl₂ (1 mL) at 0° C. The mixturewas stirred at rt for 2 h, Boc₂O (3.4 mL, 15 mmol) was added and themixture was stirred at rt for 2 h. The mixture was washed with H₂O andbrine, dried over Na₂SO₄ and filtered. The filtrate was concentrated andpurified by chromatography to give the sub-title compound (270 mg, 0.87mmol, 63%).

(b) tert-Butyl (R)-butyl(2-(4-fluorophenyl)-2-hydroxyethyl)carbamate

(S,S)—N-(p-Toluenesulfonyl)-1,2-diphenylethanediamine(chloro)(p-cymene)ruthenium(II)(16.4 mg, 0.026 mmol) (prepared as described in as described inKawamato, A. M. and Wills, M., J. Chem. Soc. Perkin 1, 1916 (2001)) wasadded to a mixture of tert-butylbutyl(2-(4-fluorophenyl)-2-oxoethyl)carbamate (200 mg, 0.65 mmol) informic acid/Et₃N (5:2, 2 mL). The mixture was stirred at rt for 64 h andH₂O (15 mL) and CH₂Cl₂ (15 mL) was added. The layers were separated andthe aq layer extracted with CH₂Cl₂. The combined organic phases werewashed with H₂O, brine, dried over Na₂SO₄ and concentrated. The residuewas purified by chromatography to give the sub-title compound (164 mg,0.53 mmol, 82%).

(c) (R)-2-(Butylamino)-1-(4-fluorophenyl)ethan-1-ol

A solution of NaOH (421 mg, 10.5 mmol) in water (1.5 mL) was added to asolution of tert-butyl(R)-butyl(2-(4-fluorophenyl)-2-hydroxyethyl)carbamate (164 mg, 0.53mmol) in EtOH (1.5 mL). The mixture was heated at 120° C. in a sealedvial for 16 h. After cooling, the pH was adjusted to 6 with HCl (1 M,aq) and the mixture extracted with EtOAc. The combined extracts weredried (Na₂SO₄), concentrated and purified by chromatography to give thetitle compound (64 mg, 0.30 mmol, 58%).

¹H NMR (400 MHz, CDCl₃): δ 7.41-7.36 (m, 2H), 7.04-6.98 (m, 2H), 5.40(dd, J=10.5, 2.6 Hz, 1H), 3.19 (dd, J=12.5, 2.6 Hz, 1H), 3.09 (dd,J=12.5, 10.5 Hz, 1H), 3.06-3.01 (m, 2H), 1.90-1.82 (m, 2H), 1.45-1.36(m, 2H), 0.91 (t, J=7.4 Hz, 3H).

Example 4: (R)-2-(Butylamino)-1-(3-fluorophenyl)ethan-1-ol

The title compound was prepared in accordance with the procedure inExample 3 from 3-fluorophenacyl bromide.

¹H NMR (400 MHz, CDCl₃): δ 7.33-7.26 (m, 1H), 7.14-7.11 (m, 2H),6.98-6.93 (m, 1H), 7.00-6.82 (br s, 3H), 4.93 (dd, J=9.9, 3.1 Hz, 1H),2.99 (dd, J=12.3, 3.1 Hz, 1H), 2.88-2.72 (m, 3H), 1.98 (s, 3H),1.63-1.56 (m, 2H), 1.40-1.31 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 5: (R)-2-(tert-Butylamino)-1-(3-fluorophenyl)ethan-1-ol

(a) (R)-2-bromo-1-(3-fluorophenyl)ethan-1-ol

Borane (1 M in THF, 0.68 mL, 0.68 mmol) was added dropwise to a mixtureof (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 0.85 mL, 0.85 mmol)and THF (0.8 mL) at rt. The mixture was stirred 15 min at rt and asolution of 3-fluorophenacyl bromide (185 mg, 0.85 mmol) in THF (1.9 mL)was added dropwise (0.09 mL/min). After 6 h at rt, MeOH (10 mL) wasadded. The mixture was stirred for 30 min and concentrated. Purificationby chromatography gave the sub-title compound (150 mg, 0.68 mmol, 80%).

(b) (R)-2-(3-fluorophenyl)oxirane

K₂CO₃ (137 mg, 0.99 mol) was added to a mixture of(R)-2-bromo-1-(3-fluorophenyl)ethan-1-ol (145 mg, 0.66 mmol) in MeOH(6.8 mL) at rt. The mixture was stirred for 30 min, filtered andconcentrated. The residue was extracted with CH₂Cl₂. The combinedextracts were concentrated to give the sub-title compound (70 mg, 0.51mmol, 77%), which was used in the next step without furtherpurification.

(c) (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol

A mixture of (R)-2-(3-fluorophenyl)oxirane (30 mg, 0.22 mmol),tert-butylamine (66 mg, 0.90 mmol) and MeOH (0.2 mL) was stirred atreflux for 16 h, cooled and concentrated and dissolved in a Et₂O.Et₂O/pentane (1:3) was added and the solution was kept at −20° C.overnight. The solid formed was collected to give the title compound (25mg, 0.12 mmol, 54%).

¹H NMR (400 MHz, CDCl₃): δ 7.33-7.26 (m, 1H), 7.14-7.09 (m, 2H),6.98-6.93 (m, 1H), 4.57 (dd, J=8.4, 3.6 Hz, 1H), 2.92 (dd, J=12.0, 4.0Hz, 1H), 2.55 (dd, J=12.0, 8.4 Hz, 1H), 1.10 (s, 9H).

Example 6: 1-(4-Amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol

(a) 1-(4-Amino-3,5-difluorophenyl)ethan-1-one

PdCl₂(MeCN)₂ (102 mg, 0.39 mmol) was added to a mixture of3,6-difluoro-4-iodoaniline (2.00 g, 7.84 mmol), ZnO (830 mg, 10.2 mol),tetrabutylammonium bromide (3.79 g, 11.8 mmol), Et₃N (0.37 mL, 2.67mmol) and DMSO (20 mL) at rt. The mixture was stirred at 100° C. inambient atmosphere for 16 h. Another portion of Et₃N (0.37 mL, 2.67mmol) was added and the heating was continued for 3 h. The mixture wasallowed to cool, diluted with Et₂O and washed with H₂O. The phases wereseparated and the aq layer was extracted with Et₂O. The combined organicphases were washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by chromatography to give the sub-title compound(270 mg, 1.58 mmol, 20%)

(b) 1-(4-Amino-3,5-difluorophenyl)-2-bromoethan-1-one

A mixture of bromine (0.16 mL, 3.15 mmol) and CHCl₃ (10 mL) was addedover 30 min to a mixture of 1-(4-amino-3,5-difluorophenyl)ethan-1-one(270 mg, 1.58 mmol) and CHCl₃ (15 mL) at reflux. After 15 min at reflux,the mixture was allowed to cool and concentrated. The residue wasdissolved in THF (6 mL) and cooled in an ice-bath. A solution ofdiethylphosphite (0.22 mL, 1.74 mmol) and Et₃N (0.24 mL, 1.74 mmol) inTHF (9 mL) was slowly added. The mixture was slowly allowed to reach rt,stirred at rt for 17 h and concentrated. Ice/water was added to theresidue and the mixture was extracted with EtOAc. The combined extractswere washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by chromatography to give the sub-title compound (250 mg,1.00 mmol, 63%).

(c) 1-(4-Amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-onehydrochloride

DIPEA (83 μL, 0.48 mmol) followed by n-butylamine (47 μL, 0.48 mmol)were added to a solution of1-(4-amino-3,5-difluorophenyl)-2-bromoethan-1-one (100 mg, 0.40 mmol) inCHCl₃ (1 mL) at rt. The mixture was heated at 75° C. for 1 h and allowedto cool to 40-50° C. when HCl (1 M in Et₂O, 560 μL, 0.56 mmol) wasadded. The mixture was cooled to rt and the solid collected to give thesub-title compound (44 mg, 0.16 mmol, 40%), which was used in the nextstep without further purification.

(d) 1-(4-Amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol

NaOH (1 M, ˜0.15 mL) was added to a mixture of1-(4-amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-one hydrochloride(40 mg, 0.14 mmol), MeOH (0.2 mL) and H₂O (0.3 mL) to adjust the pH to9. A solution of NaBH₄ (10.9 mg, 0.29 mmol) in H₂O was added dropwiseand the mixture was stirred at rt for 2 h. The mixture was concentratedto remove the MeOH. Water was added and the mixture was extracted withCH₂Cl₂. The combined extracts were washed with brine, dried over Na₂SO₄and concentrated. The residue was dissolved in Et₂O (1 mL). Pentane (5mL) was added and the solid was collected to give the sub-title compound(20 mg, 0.082 mmol, 57%)

¹H NMR (400 MHz, CDCl₃): δ 6.89-6.80 (m, 2H), 4.54 (dd, J=8.8, 3.4 Hz,1H), 3.75-3.60 (br s, 2H), 2.84 (dd, J=12.1, 3.4 Hz, 1H), 2.70-2.57 (m,3H), 2.73-2.03 (br s, 2H, overlapping), 1.51-1.41 (m, 2H), 1.40-1.29 (m,2H), 0.92 (t, J=7.4 Hz, 3H).

Example 7: 1-(3-Amino-2,4-difluorophenyl)-2-(butylamino)ethan-1-ol

(a) N-(2,6-Difluoro-3-methylphenyl)acetamide

A mixture of 2,6-difluoro-3-methylaniline (4 g, 27.9 mmol) and aceticanhydride (5.3 mL) was heated at 60° C. for 2 h. Water was added and themixture was extracted with CH₂Cl₂. The combined extracts were washedwith brine, dried over Na₂SO₄ and concentrated. Purification bychromatography gave the sub-title compound (5.1 g, 27.5 mmol, 99%).

(b) 3-Acetamido-2,4-difluorobenzoic acid

KMnO₄ (10.7 g, 67.7 mmol) was added cautiously to a mixture ofN-(2,6-difluoro-3-methylphenyl)acetamide (2.5 g, 13.5 mmol), pyridine(20 mL) and H₂O (70 mL) at 70° C. The mixture was heated at reflux for10 h, filtered while hot through a pad of Celite and the pad was washedwith hot H₂O. The filtrates were cooled to rt, concentrated andcarefully acidified with HCl (aq, 6 M). The mixture was cooled in anice-bath and filtered. The solids were washed with cold H₂O, dried andpurified by chromatography to give the sub-title compound (2.1 g, 9.76mmol, 72%).

(c) N-(3-(2-Bromoacetyl)-2,6-difluorophenyl)acetamide

A mixture of 3-acetamido-2,4-difluorobenzoic acid (1.1 g, 5.11 mmol),SOCl₂ (8 mL) and CH₂Cl₂ (20 mL) was stirred at rt for 2 h, concentratedand dried in vacuo. The residue was dissolved in CH₂Cl₂ (60 mL) andtrimethylsilyl diazomethane (5.1 mL, 10.2 mmol) was added dropwise at 0°C. The mixture was allowed to come to rt over 4 h and cooled to 0° C.HBr (33% in AcOH, 2.8 mL) was added dropwise. The mixture was allowed tocome to rt over 2.5 h, diluted with CH₂Cl₂ and washed NaHCO₃ (aq, sat)and NH₄Cl (aq, sat) and dried over MgSO₄ and concentrated to give aquantitative yield of the sub-title compound, which was used in the nextstep without further purification.

(d) 1-(3-Amino-2,4-difluorophenyl)-2-bromoethan-1-one

HBr (aq, 48%, 0.05 mL) was added toN-(3-(2-bromoacetyl)-2,6-difluorophenyl)acetamide (70 mg, 0.24 mmol) atrt. The mixture was heated to 100° C. and stirred at that temperaturefor 40 min, cooled and poured into H₂O. The mixture was extracted withEtOAc and the combined extracts were washed with H₂O, NaHCO₃ (aq, sat),brine and dried over MgSO₄. Concentration gave the sub-title compound(50 mg, 0.20 mmol, 83%).

(e) 2,6-Difluoro-3-(oxiran-2-yl)aniline

NaBH₄ (3.78 mg, 0.10 mmol) was added to a mixture of1-(3-mino-2,4-difluorophenyl)-2-bromoethan-1-one (50 mg, 0.20 mmol) at0° C. The cooling bath was removed and the mixture was stirred at rt for1 h. MeOH (1 mL) and K₂CO₃ (41.5 mg, 0.30 mmol) were added and themixture was stirred at rt for 3 h and concentrated. Water was added tothe residue and the mixture was extracted with CH₂Cl₂ and the combinedextracts were washed with H₂O, brine, dried over MgSO₄ and filteredthrough neutral alumina. Concentration gave the sub-title compound (20mg, 0.12 mmol, 58%).

(f) 1-(3-Amino-2,4-difluorophenyl)-2-(butylamino)ethan-1-ol

A mixture of 2,6-difluoro-3-(oxiran-2-yl)aniline (30 mg, 0.18 mmol),n-butylamine (12.8 mg, 0.18 mmol) and EtOH (0.9 mL) was stirred at 50°C. for 18 h. The mixture was concentrated and the residue purified bychromatography to give the title compound (22 mg, 0.09 mmol, 51%).

¹H NMR (400 MHz, CDCl₃): δ 6.90-6.72 (m, 2H), 4.97 (dd, J=8.8, 3.6 Hz,1H), 3.70 (s, 2H), 2.94 (dd, J=13.0, 3.6 Hz, 1H), 2.72-2.58 (m, 3H),1.52-1.30 (m, 4H), 0.92 (t, J=7.2 Hz, 3H).

Example 8:N-(3-(2-(Butylamino)-1-hydroxyethyl)-2,6-difluorophenyl)acetamide

The title compound was prepared fromN-(3-(2-bromoacetyl)-2,6-difluorophenyl)-acetamide (see Example 7, Step(c)) in accordance with the procedures in Example 7, Steps (e) and (f).

¹H NMR (400 MHz, THF-d₈): δ 8.69 (br s, 1H), 7.41 (q, J=8.2 Hz, 1H),6.92 (t, J=8.8 Hz, 1H), 4.93 (dd, J=8.6, 3.2 Hz, 1H), 2.76 (ddd, J=8.4,4.8, 3.6 Hz 1H), 2.66-2.56 (m, 3H), 2.04 (s, 3H), 1.48-1.29 (m, 4H),0.90 (t, J=7.2 Hz, 3H).

Example 9: 1-(4-Amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol

(a) 3-Amino-2-fluoroacetophenone

Fe powder (595 mg, 10.6 mmol) followed by NH₄Cl (570 mg, 10.6 mmol) inH₂O (1.2 mL) were added to a solution of 2-fluoro-3-nitroacetophenone at55° C. The mixture was heated at reflux for 2.5 h, cooled to rt andfiltered through Celite. NaHCO₃ (aq, sat) was added to the filtrate,which then was extracted with EtOAc. The combined extracts were washedwith brine, dried over MgSO₄ and concentrated. The residue was extractedwith hexane and the extract concentrated. The residue was extracted withhexane/Et₂O (10:1) and the extract concentrated to give the sub-titlecompound (350 mg, 2.28 mmol, 84%).

(b) N-(3-Acetyl-2-fluorophenyl)acetamide

The sub-title compound was prepared in accordance with the procedure inExample 7, Step (a) from 3-amino-2-fluoroacetophenone.

(c) N-(3-(2-Bromoacetyl)-2,6-difluorophenyl)acetamide

CuBr (652 mg, 2.92 mmol) was added to a solution ofN-(3-acetyl-2-fluorophenyl)-acetamide (380 mg, 1.95 mmol) in EtOAc (4.8mL) at rt. The mixture was heated at reflux for 20 h, allowed to cooland extracted with EtOAc. The combined extracts were washed with brine,dried over MgSO₄, filtered through neutral alumina and concentrated. Theresidue was purified by chromatography to give the sub-title compound(135 mg, 0.49 mmol, 25%).

(d) 1-(4-Amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol

The title compound was prepared fromN-(3-(2-bromoacetyl)-2,6-difluorophenyl)-acetamide in accordance withthe procedures in Example 7, Steps (d), (e) and (f).

¹H NMR (400 MHz, CDCl₃): δ 6.93 (dd, J=11.0, 8.2 Hz, 1H), 6.82 (dd,J=8.6, 2.2 Hz, 1H), 6.67-6.64 (m, 1H), 4.58 (dd, J=9.0, 3.8 Hz, 1H),3.71 (s, 2H), 2.86 (dd, J=12.0, 3.6 Hz, 1H), 2.70-2.60 (m, 3H),1.51-1.30 (m, 4H), 0.92 (t, J=7.4 Hz, 3H).

Examples 10 and 11:(R)-1-(4-Fluorophenyl)-2-(((R)-pentan-2-yl)amino)ethan-1-ol and(R)-1-(4-Fluorophenyl)-2-(((S)-pentan-2-yl)amino)ethan-1-ol

(a) tert-Butyl (2-(4-fluorophenyl)-2-oxoethyl)(pentan-2-yl)carbamate

A solution of 4-fluorophenacyl bromide (500 mg, 2.31 mmol) in CH₂Cl₂(6.6 mL) was added over 10 min to a solution of 2-aminopentane (301 mg,3.46 mmol) and DIPEA (298 mg, 2.31 mmol) in CH₂Cl₂ (1.6 mL) at 0° C. Thecooling bath was removed and the mixture was stirred at rt for 2 h. Asolution of Boc₂O (1.26 g, 5.76 mmol) in CH₂Cl₂ (6 mL) was added and themixture was stirred at rt for 2 h, washed with H₂O, brine and dried overNa₂SO₄. Concentration and purification by chromatography gave thesub-title compound (520 mg, 1.61 mmol, 70%).

(b) (R)-1-(4-Fluorophenyl)-2-(((R)-pentan-2-yl)amino)ethan-1-ol and(R)-1-(4-Fluorophenyl)-2-(((S)-pentan-2-yl)amino)ethan-1-ol

The title compounds were obtained using the procedure in Example 3, Step(b) followed by chromatographic separation and hydrolysis of theindividual Boc-protected intermediates in accordance with the procedurein Example 3, step (c).

¹H NMR (400 MHz, CDCl₃): δ 7.34 (dd, J=8.4, 5.6 Hz, 2H), 7.03 (t, J=8.4Hz, 2H), 4.61 (dd, J=9.4, 3.4 Hz, 1H), 2.91 (dd, J=12.0, 3.6 Hz, 1H),2.69-2.59 (m, 2H), 1.47-1.28 (m, 4H), 1.06 (d, J=6.0 Hz, 3H), 0.91 (t,J=6.8 Hz, 3H).

and

7.42 (dd, J=8.4, 5.6 Hz, 2H), 7.03 (t, J=8.8 Hz, 2H), 5.40 (dd, J=10.4,2.4 Hz, 1H), 3.28-3.21 (m, 2H), 2.99 (t, J=11.2 Hz, 1H), 1.94-1.85 (m,1H), 1.72-1.63 (m, 1H), 1.51-1.34 (m, 5H), 0.91 (t, J=7.4 Hz, 3H).

Examples 12 and 13:(R)-1-(3-fluorophenyl)-2-(((R)-pentan-2-yl)amino)ethan-1-ol and(R)-1-(3-fluorophenyl)-2-(((S)-pentan-2-yl)amino)ethan-1-ol

The title compounds were prepared in accordance with Examples 10 and 11from 3-fluorophenacyl bromide.

¹H NMR (400 MHz, CDCl₃): δ 7.33-7.26 (m, 1H), 7.14-7.09 (m, 2H),7.00-6.90 (m, 1H), 4.66 (dd, J=8.8, 3.6 Hz, 1H), 2.97-2.92 (m, 1H),2.72-2.62 (m, 3H), 1.47-1.26 (m, 4H), 1.07 (dd, J=6.4, 1.2 Hz, 3H),0.93-0.89 (m, 3H).

and

7.33-7.27 (m, 1H), 7.21-7.18 (m, 2H), 7.00-6.96 (m, 1H), 5.40 (dd,J=10.4, 2.4 Hz, 1H), 3.31-3.20 (m, 2H), 2.98 (t, J=11.4, Hz, 1H),1.93-1.85 (m, 1H), 1.72-1.62 (m, 1H), 1.50-1.33 (m, 5H), 0.91 (t, J=7.4Hz, 3H).

Example 14: (R)-1-(3-Fluorophenyl)-2-((2-methylpentan-2-yl)amino)ethan-1-ol

A mixture of (R)-2-(3-fluorophenyl)oxirane (40 mg, 0.29 mmol),2-methylpentan-2-amine hydrochloride (80 mg, 0.58 mmol), DIPEA (0.1 mL,0.58 mmol) and MeOH (0.3 mL) was stirred at reflux for 16 h, cooled andconcentrated. The residue was purified by chromatography andcrystallization from Et₂O/hexane (1:4) to give the title compound (10mg, 0.042 mmol, 14%).

¹H NMR (400 MHz, CDCl₃): δ 7.32-7.27 (m, 1H), 7.19-7.09 (m, 2H),6.98-6.93 (m, 1H), 4.85 (dd, J=9.2, 3.2 Hz, 1H), 4.07 (br s, 1H), 2.99(dd, J=11.8, 3.4 Hz, 1H), 2.66 (dd, J=12.2, 9.4 Hz, 1H), 1.48-1.27 (m,4H), 1.18 (d, J=3.6 Hz, 6H), 0.91 (t, J=7.2 Hz, 3H).

Example 15: (R)-2-(tert-Butylamino)-1-(2,3-difluorophenyl)ethan-1-ol

(a) 2-Bromo-1-(2,3-difluorophenyl)ethan-1-one

Trimethylphenylammonium tribromide (1.59 g, 4.22 mmol) was added inportions to a stirred solution of 2,3-difluoroacetophenone (0.60 g, 3.84mmol) in CH₂Cl₂ (10 mL) at rt. The mixture was stirred at rt overnight,diluted with CH₂Cl₂ and poured into water. The layers were separated andthe aq phase was extracted with CH₂Cl₂. The combined extracts were dried(Na₂SO₄), filtered and concentrated. The residue was purified bychromatography to give the sub-title compound (0.80 g, 3.40 mmol, 89%).

(b) 2-Chloro-1-(2,3-difluorophenyl)ethan-1-one

NaCl (aq., sat, 4 mL) was added to a solution of2-bromo-1-(2,3-difluorophenyl)ethan-1-one (600 mg, 2.55 mmol) in THF (10mL) at rt. The mixture was heated in a sealed tube at 70° C. for 16 hand allowed to cool. The mixture was diluted with EtOAc (100 mL) andbrine and the layers separated. The aq phase was extracted with EtOAcand the combined organic phases dried (Na₂SO₄), filtered andconcentrated. The residue was purified by chromatography to give thesub-title compound (350 mg, 1.84 mmol, 72%).

(c) (R)-2-Chloro-1-(2,3-difluorophenyl)ethan-1-ol

RhClCp*[(1S,2S)-p-TsNCH(C₆H₅)CH(C₆H₅(CeH)NH₂]/HCl.Et₃N (20.4 mg, 26pmol), prepared from dichloro(pentamethylcyclopentadienyl)rhodium (III)dimer, (1S,2S)-(+)—N-(4-toluene-sulphonyl)-1,2-diphenylethylene diamineand Et₃N as described in WO 2008/054155, was added to a mixture of2-chloro-1-(2,3-difluorophenyl)ethan-1-one (500 mg, 2.62 mmol) in THF(10 mL). Formic acid/Et₃N (5:2, 1 mL) was added and the mixture wasstirred at rt for 80 min. The mixture was diluted with EtOAc, washedtwice with H₂O, dried (Na₂SO₄), filtered and concentrated. The residuewas purified by chromatography to give the sub-title compound (420 mg,2.18 mmol, 83%, ee=88%).

(d) (R)-2-(2,3-Difluorophenyl)oxirane

NaOH (aq, 1 M, 5.9 mL, 5.9 mmol) was added dropwise to a solution of(R)-2-chloro-1-(2,3-difluorophenyl)ethan-1-ol (380 mg, 1.97 mmol) iniPrOH (4 mL) at 0° C. The mixture was diluted with Et₂O and the layersseparated. The aq phase was extracted with Et₂O and the combined organicphases dried (Na₂SO₄), filtered and carefully concentrated. The productis volatile and the material was a ˜1:1 mixture of the sub-titlecompound and iPrOH, and was used in the next step without furtherpurification.

(e) (R)-2-(tert-Butylamino)-1-(2,3-difluorophenyl)ethan-1-ol

A mixture of (R)-2-(2,3-difluorophenyl)oxirane (200 mg, 1.28 mmol,containing iPrOH) and tert-butylamine (0.30 mL, 2.8 mmol) was stirred at70° C. for 16 h, cooled and concentrated. The residue was treated withEt₂O/pentane (3+10 mL) at −20° C. and the solids collected and washedwith cold Et₂O/pentane to give the title compound (135 mg, 0.59 mmol,46%, ee=88%).

1H NMR (400 MHz, CDCl₃): δ 7.35-7.28 (m, 1H), 7.12-7.00 (m, 2H), 4.91(dd, J=8.4, 3.7 Hz, 1H), 3.00 (ddd, J=12.0, 3.7, 1.1 Hz, 1H), 3.0-2.0(br s 2H), 2.55 (ddd, J=12.1, 8.4, 0.7 Hz, 1H), 1.11 (s, 9H).

Example 16: (R)-2-(Butylamino)-1-(2,3-difluorophenyl)ethan-1-ol

A mixture of (R)-2-(2,3-difluorophenyl)oxirane (200 mg, 1.28 mmol,containing iPrOH) and n-butylamine (2.5 mL, 25.6 mmol) was heated undermicrowave irradiation at 100° C. for 1 h The residue was concentratedand purified by chromatography to give the title compound (220 mg, 0.96mmol, 75%).

¹H NMR (400 MHz, CDCl₃): δ 7.34-7.27 (m, 1H), 7.12-7.00 (m, 2H), 5.01(dd, J=8.8, 3.5 Hz, 1H), 3.03-2.92 (m, 1H), 2.90-2.40 (br s, 2H),2.74-2.57 (m, 3H), 1.54-1.41 (m, 2H), 1.41-1.27 (m, 2H), 0.91 (t, J=7.3Hz, 3H).

Example 17: (R)-2-(tert-Butylamino)-1-(2-fluorophenyl)ethan-1-ol

The title compound was prepared in accordance with the procedure inExample 15, Step (f), from (R)-2-(2-fluorophenyl)oxirane andtert-butylamine.

¹H NMR (300 MHz, CDCl₃): δ 7.56 (m, 1H), 7.19-7.28 (m, 1H), 7.16 (m,1H), 6.97-7.05 (ddd, J=10.5, 8.1, 1.3 Hz, 1H), 4.92 (dd, J=8.5, 3.8 Hz,1H), 3.00 (ddd, J=11.9, 3.8, 0.9 Hz, 1H), 2.57 (dd, J=11.7, 8.5 Hz, 1H),1.85-2.57 (bs, 2H), 1.12 (s, 9H)

Example 18: (R)-2-(Butylamino)-1-(2-fluorophenyl)ethan-1-ol

The title compound was prepared in accordance with the procedure inExample 16 from (R)-2-(2-fluorophenyl)oxirane and n-butylamine.

¹H NMR (300 MHz, CDCl₃): δ 7.60-7.51 (m, 1H), 7.29-7.20 (m, 1H),7.19-7.12 (m, 1H), 7.00 (ddd, J=10.6, 8.1, 1.3 Hz, 1H), 5.02 (dd, J=8.8,3.6 Hz, 1H), 2.99 (ddd, J=12.2, 3.6, 1.1 Hz, 1H), 2.80-2.54 (m, 3H),2.52-2.09 (bs, 2H), 1.54-1.42 (m, 2H), 1.42-1.30 (m, 2H), 0.92 (t, J=7.2Hz, 3H).

Example 19: (R)-2-(2-(tert-Butylamino)-1-hydroxyethyl)-5-fluorophenolacetate

(a) 1-(2-(Benzyloxy)-4-fluorophenyl)ethan-1-one

A mixture of 4-fluoro-2-hydroxyacetophenone (319 mg, 2.07 mmol),benzylbromide (0.29 mL, 2.48 mmol), K₂CO₃ (572 mg, 4.14 mmol) andacetone (12 mL) was stirred at rt for 24 h and filtered. The filtratewas concentrated and the residue purified by chromatography to give thesub-title compound (501 mg, 2.05 mmol, 99%).

(b) 1-(2-(Benzyloxy)-4-fluorophenyl)-2-bromoethan-1-one

Bromine (0.12 mL, 2.30 mmol) was added in portions to a mixture of1-(2-(benzyloxy)-4-fluorophenyl)ethan-1-one (562 mg, 2.30 mmol) in Et₂O(20 mL) at rt. After 30 min another portion of bromine (0.06 mL, 1.15mmol) was added and the mixture stirred at rt for 90 min. The mixturewas concentrated and THF (5 mL) was added. The mixture was cooled in anice-bath and a mixture of diethylphosphite (0.30 mL, 2.30 mmol) and Et₃N(0.32 mL, 2.30 mmol) was added. The ice-bath was removed and the mixturestirred at rt for 60 min. Ice was added to the mixture, which was leftto stir overnight. The mixture was diluted with CH₂Cl₂ and the phasesseparated. The aq phase was extracted with CH₂Cl₂ and the combinedorganic phases dried (Na₂SO₄), filtered and concentrated. The residuewas purified by chromatography to give the sub-title compound (700 mg,2.17 mmol, 94%).

(c) (R)-1-(2-(Benzyloxy)-4-fluorophenyl)-2-bromoethan-1-ol

The sub-title compound was prepared from1-(2-(benzyloxy)-4-fluorophenyl)-2-bromoethan-1-one in accordance withthe procedure in Example 5, Step (a).

(d) (R)-2-(2-(Benzyloxy)-4-fluorophenyl)oxirane

The sub-title compound was prepared from(R)-1-(2-(benzyloxy)-4-fluorophenyl)-2-bromoethan-1-ol in accordancewith the procedure in Example 5, Step (b).

(e) (R)-1-(2-(Benzyloxy)-4-fluorophenyl)-2-(tert-butylamino)ethan-1-ol

A mixture of (R)-2-(2-(benzyloxy)-4-fluorophenyl)oxirane (190 mg, 0.78mmol), n-butyl-amine (0.180 mL, 1.71 mmol) and MeOH (0.6 mL) was stirredat 70° C. for 3 h. The mixture was concentrated and the residue purifiedby chromatography to give the sub-title compound (135 mg, 0.42 mmol,55%).

(f) (R)-2-(2-(tert-Butylamino)-1-hydroxyethyl)-5-fluorophenol acetate

A mixture of(R)-1-(2-(benzyloxy)-4-fluorophenyl)-2-(tert-butylamino)ethan-1-ol (157mg, 0.49 mmol), Pd—C(10%, 52.6 mg, 0.05 mmol) and AcOH (4 mL) washydrogenated at 6 bar for 2 h. The mixture was filtered through Celite,concentrated and purified by chromatography. The material was dissolvedin AcOH (1%) in MeOH and Et₂O was added. The mixture was kept at −20° C.for 2 d and the solids were collected and washed with Et₂O to give thetitle compound (60 mg, 0.21 mmol, 42%).

¹H NMR (400 MHz, D₂O): δ 7.40 (dd, J=8.6, 6.7 Hz, 1H), 6.84-6.65 (m,2H), 5.21 (dd, J=9.4, 3.2 Hz, 1H), 3.37 (dd, J=12.8, 3.2 Hz, 1H), 3.25(dd, J=12.7, 9.4 Hz, 1H), 1.94 (s, OH), 1.41 (s, 9H).

Example 20: (R)-2-(2-(Butylamino)-1-hydroxyethyl)-5-fluorophenol acetate

(a) (R)-(1-(2-(Benzyloxy)-4-fluorophenyl)-2-bromoethoxy)triethylsilane

Chlorotriethylsilane (0.12 mL, 0.73 mmol) was added in one portion to amixture of (R)-1-(2-(benzyloxy)-4-fluorophenyl)-2-bromoethan-1-ol (215mg, 0.66 mmol) (See Example 19, Step (c)), imidazole (58.5 mg (0.86mmol) and DMF (5 mL) at 5° C. The temperature was allowed to reach 15°C. and the mixture was stirred at that temperature for 1 h. The mixturewas diluted with petroleum ether, washed three times with H₂O, dried(Na₂SO₄), filtered and concentrated to give the sub-title compound (270mg, 0.61 mmol, 93%).

(b) (R)—N-(2-(2-(benzyloxy)-4-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)butan-1-amine

A mixture of(R)-(1-(2-(benzyloxy)-4-fluorophenyl)-2-bromoethoxy)triethylsilane (270mg, 0.61 mmol), n-butylamine (0.30 mL, 3.07 mmol) and dioxane (2 mL) washeated at 80° C. for 16 h. Another portion of n-butylamine (0.30 mL,3.07 mmol) was added and the mixture was heated at 105° C. for 48 h. Themixture was allowed to cool and H₂O and Et₂O was added. The organiclayer was collected and washed three times with NH₄Cl (aq, sat), NaHCO₃(aq, sat) and brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was dissolved in THF (3 mL) and tributylammoniumfluoride (1 M inTHF, 0.74 mL, 0.74 mmol) was added dropwise at 5° C. The mixture wasstirred at 50° C. for 20 min, allowed to cool and H₂O and Et₂O wasadded. The organic layer was collected and washed with H₂O (aq, sat) andbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by chromatography to give the sub-title compound (94 mg, 0.30mmol, 48%).

(c) (R)-2-(2-(Butylamino)-1-hydroxyethyl)-5-fluorophenol acetate

The title compound was prepared from(R)-1-(2-(benzyloxy)-4-fluorophenyl)-2-(butylamino)ethan-1-ol inaccordance with the procedure in Example 19 Step (f).

¹H NMR (400 MHz, D₂O): δ 7.40 (dd, J=8.6, 6.7 Hz, 1H), 6.80-6.68 (m,2H), 5.26 (dd, J=8.7, 3.9 Hz, 1H), 3.38 (dd, J=13.0, 4.0 Hz, 1H), 3.32(dd, J=12.9, 8.7 Hz, 1H), 3.17-3.09 (m, 2H), 1.94 (s, 3H), 1.71 (tt,J=7.9, 6.5 Hz, 2H), 1.41 (h, J=7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).

Example 21: (R)-1-(3-fluorophenyl)-2-((1-methylcyclobutyl)amino)ethan-1-ol

A mixture of (R)-2-(2-fluorophenyl)oxirane (130 mg, 0.94 mmol),(1-metylcyclobutyl)amine hydrochloride (298 mg, 2.45 mmol), DIPEA (0.33mL, 1.88 mmol) and iPrOH (0.5 mL) was stirred at 70° C. for 3 h, cooledand poured into NaHCO₃ (aq., sat). The mixture was extracted with EtOAcand the combined extracts were dried (Na₂CO₃) and concentrated. Theresidue was purified by chromatography to give the title compound (60mg, 0.27 mmol, 29%).

¹H NMR (400 MHz, CDCl₃): δ 7.30 (td, J=8.1, 5.9 Hz, 1H), 7.15-7.09 (m,2H), 6.99-6.92 (m, 1H), 4.66 (dd, J=8.7, 3.6 Hz, 1H), 2.90 (dd, J=12.1,3.7 Hz, 1H), 2.56 (dd, J=12.1, 8.7 Hz, 1H), 2.5-2.0 (br s, 2H),2.03-1.90 (m, 2H), 1.87-1.69 (m, 4H), 1.28 (s, 3H).

Example 22: (R)-1-(3-fluorophenyl)-2-((1-methylcyclopropyl)amino)ethan-1-ol

The title compound was prepared according to Example 21 from(R)-2-(2-fluorophenyl)-oxirane and (1-metylcyclopropyl)aminehydrochloride.

¹H NMR (300 MHz, CDCl₃): δ 77.35-7.27 (m, 1H), 7.17-7.06 (m, 2H), 6.95(td, J=8.5, 2.6 Hz, 1H), 4.60 (dd, J=8.7, 3.6 Hz, 1H), 3.08 (dd, J=12.1,3.7 Hz, 1H), 2.67 (dd, J=12.1, 8.7 Hz, 1H), 2.6-2.0 (br s, 2H), 1.25 (s,3H), 0.70-0.53 (m, 2H), 0.48-0.33 (m, 2H).

Example 23: (R)-5-(2-(tert-Butylamino)-1-hydroxyethyl)-2-fluorophenolacetate

¹H NMR (400 MHz, D₂O): δ 7.25-7.14 (m, 1H), 7.12-7.01 (m, 1H), 7.01-6.89(m, 1H), 4.92 (dd, J=3.2, 9.8 Hz, 1H), 3.33-3.14 (m, 2H), 1.92 (s, 3H),1.40 (s, 9H).

Example 24: (R)-5-(2-(Butylamino)-1-hydroxyethyl)-2-fluorophenol acetate

¹H NMR (400 MHz, D₂O): δ 7.25-7.13 (m, 1H), 7.10-7.01 (m, 1H), 6.98-6.89(m, 1H), 4.98 (dd, J=4.0, 9.0 Hz, 1H), 3.37-3.20 (m, 2H), 3.19-3.03 (m,2H), 1.92 (s, 3H), 1.75-1.61 (m, 2H), 1.47-1.31 (m, 2H), 0.93 (t, J=7.4Hz, 3H)

Example 25: (R)-3-(2-(tert-Butylamino)-1-hydroxyethyl)-2-fluorophenol

(a) 1-(3-(Benzyloxy)-2-fluorophenyl)ethan-1-one

The sub-title compound was prepared from 4-fluoro-2-hydroxyacetophenoneand benzylbromide in accordance with the procedure in Example 20, Step(a).

(b) 1-(3-(Benzyloxy)-2-fluorophenyl)-2-bromoethan-1-one

A mixture of bromine (0.13 mL, 2.45 mmol) and Et₂O (2 mL) was addeddropwise to a mixture of 1-(3-(benzyloxy)-2-fluorophenyl)ethan-1-one(599 mg, 2.45 mmol) and Et₂O (18 mL) at rt. After 10 min the mixture waswashed with NaHSO₄ (aq., sat) and brine and dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography to give thesub-title compound (600 mg, 1.86 mmol, 76%).

(c) (R)-1-(3-(Benzyloxy)-2-fluorophenyl)-2-bromoethan-1-ol

The sub-title compound was prepared from1-(3-(benzyloxy)-2-fluorophenyl)-2-bromoethan-1-one e in accordance withthe procedure in Example 5, Step (a).

(d) (R)-1-(3-(Benzyloxy)-2-fluorophenyl)-2-(tert-butylamino)ethan-1-ol

NaOH (18.45 mg, 0.46 mmol) was added to a mixture of(R)-1-(3-(benzyloxy)-2-fluorophenyl)-2-bromoethan-1-ol (150 mg, 0.46mmol), tert-butylamine (0.49 mL, 4.61 mmol) and MeOH (0.2 mL) at rt. Themixture was heated at 70° C. for 16 h, cooled to rt, diluted with EtOAc,washed with water, dried over Na₂SO₄ and concentrated. The residue waspurified by chromatography to give the sub-title compound (120 mg, 0.38mmol, 82%).

(e) (R)-3-(2-(tert-Butylamino)-1-hydroxyethyl)-2-fluorophenol

Et₃SiH (0.60 mL, 3.78 mmol) was added dropwise to a mixture of(R)-1-(3-(benzyloxy)-2-fluorophenyl)-2-(tert-butylamino)ethan-1-ol (120mg, 0.38 mmol), Pd—C(10%, 80.5 mg, 0.08 mmol) and MeOH (1 mL) at rt. Themixture was stirred at rt for 10 min, filtered through Celite,concentrated and purified by chromatography. The material was trituratedwith Et₂O to give the title compound (56 mg, 0.25 mmol, 65%).

¹H NMR (400 MHz, CD₃OD): δ 7.04-6.95 (m, 2H), 6.91-6.84 (m, 1H), 5.14(dd, J=9.7, 3.3 Hz, 1H), 3.00 (ddd, J=12.0, 3.3, 0.6 Hz, 1H), 2.91 (dd,J=12.0, 9.7 Hz, 1H), 1.28 (s, 9H).

Example 26: (R)-3-(2-(Butylamino)-1-hydroxyethyl)-2-fluorophenol

(a) (R)-1-(3-(Benzyloxy)-2-fluorophenyl)-2-(butylamino)ethan-1-ol

The sub-title compound was prepared from(R)-1-(3-(benzyloxy)-2-fluorophenyl)-2-bromoethan-1-ol in accordancewith the procedure in Example 25, Step (d).

(b) (R)-3-(2-(Butylamino)-1-hydroxyethyl)-2-fluorophenol

The title compound was prepared from(R)-1-(3-(benzyloxy)-2-fluorophenyl)-2-(butylamino)ethan-1-ol inaccordance with the procedure in Example 25, Step (e)

¹H NMR (400 MHz, CDCl₃): δ 6.96-6.88 (m, 2H), 6.86-6.81 (m, 1H), 5.07(dd, J=8.9, 3.6 Hz, 1H), 4.43 (br s, 3H), 2.92 (dd, J=12.1, 3.6 Hz, 1H),2.78 (dd, J=12.1, 8.8 Hz, 1H), 2.72-7.59 (m, 2H), 1.54-1.40 (m, 2H),1.36-1.27 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).

Example 27: (R)-1-(3-Amino-2-fluorophenyl)-2-(tert-butylamino)ethan-1-ol

(a) 2-Fluoro-3-isobutyramidobenzoic acid

A mixture of 3-amino-2-fluorobenzoic acid (2.00 g; 12.9 mmol),isobutyric anhydride (4.3 mL, 25.8 mmol) and CH₂Cl₂ was heated at 50° C.for 2 h. The mixture was allowed to cool and concentrated. Purificationof the residue by chromatography gave the sub-title compound (1.24 g,5.51 mmol, 43%).

(b) N-(3-(2-Bromoacetyl)-2-fluorophenyl)isobutyramide

A mixture of 2-fluoro-3-isobutyramidobenzoic acid (300 mg, 1.33 mmol),SOCl₂ (1.9 mL) and dioxane (3 mL) was heated at 50° C. for 12 h,concentrated and dried in vacuo. The residue was dissolved in CH₂Cl₂ (15mL) and trimethylsilyl diazomethane (1.33 mL, 2.66 mmol) was addeddropwise at 0° C. The mixture was stirred at rt for 2 h and cooled to 0°C. HBr (33% in AcOH, 0.91 mL) was added dropwise. The mixture wasstirred at 0° C. for 30 min and at rt for 2 h. NaHCO₃ (aq, sat) wasadded until the pH was ˜7. Purification of the residue by chromatographygave the sub-title compound (0.22 mg, 0.73 mmol, 55%).

(c) (R)—N-(3-(2-bromo-1-hydroxyethyl)-2-fluorophenyl)isobutyramide

The sub-title compound was prepared fromN-(3-(2-Bromoacetyl)-2-fluorophenyl)-isobutyramide in accordance withthe procedure in Example 5, Step (a).

(d)(R)—N-(3-(2-(tert-butylamino)-1-hydroxyethyl)-2-fluorophenyl)isobutyramide

A mixture of(R)—N-(3-(2-bromo-1-hydroxyethyl)-2-fluorophenyl)isobutyramide (240 mg,0.79 mmol), tert-butylamine (0.83 mL, 7.89 mmol), NaOH (31.6 mg, 0.79mmol) and iPrOH (0.60 mL, 7.89 mmol) was heated at 65° C. for 3 h,cooled to rt, diluted with EtOAc, washed with water, dried over Na₂SO₄and concentrated. The residue was purified by chromatography to give thesub-title compound (180 mg, 0.61 mmol, 77%).

(e) (R)-1-(3-Amino-2-fluorophenyl)-2-(butylamino)ethan-1-oldihydrochloride

A mixture of(R)—N-(3-(2-(tert-butylamino)-1-hydroxyethyl)-2-fluorophenyl)isobutyramide(55 mg, 0.19 mmol) and HCl (1 M, aq, 1 mL) was heated at 85° C. for 3 h,concentrated and dried to give the title compound (50 mg, 0.17 mmol,90%), ee=94%.

¹H NMR (400 MHz, CD₃OD): δ 6.94 (td, J=7.8, 1.0 Hz, 1H), 6.81 (dddd,J=14.7, 9.4, 7.2, 1.8 Hz, 2H), 5.05 (t, J=6.4 Hz, 1H), 2.78 (d, J=6.4Hz, 2H), 1.17 (s, 9H).

Example 28: (R)-1-(3-Amino-2-fluorophenyl)-2-(butylamino)ethan-1-oldihydrochloride

The title compound was prepared in accordance with the procedures inExample 27, using n-butylamine and MeOH in Step (d).

¹H NMR (400 MHz, D₂O): δ 7.62 (td, J=7.4, 6.7, 1.7 Hz, 1H), 7.49 (td,J=7.8, 1.7 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 5.39 (dd, J=9.4, 3.6 Hz,1H), 3.42 (dd, J=13.2, 3.8 Hz, 1H), 3.36 (dd, J=13.2, 9.5 Hz, 1H),3.21-3.12 (m, 2H), 1.72 (tt, J=7.9, 6.5 Hz, 2H), 1.42 (h, J=7.4 Hz, 2H),0.95 (t, J=7.4 Hz, 3H).

Example 29: (R)-1-(3-Fluorophenyl)-2-(neopentylamino)ethan-1-olhydrochloride

A mixture of (R)-2-(3-fluorophenyl)oxirane (60 mg, 0.43 mmol) andneopentylamine (379 mg, 4.34 mmol) was heated at 75° C. overnight andconcentrated. The residue was dissolved in Et₂O (5 mL) and HCl (2 M inEt₂O, 0.17 mL, 0.35 mmol) was added. The solids were collected and driedto give the title compound (92 mg, 0.35 mmol, 81%).

¹H NMR (400 MHz, D₂O): δ 7.50-7.44 (m, 1H), 7.28-7.20 (m, 2H), 7.19-7.12(m, 1H), 5.16 (dd, J=10.0, 3.7 Hz, 1H), 3.38 (dd, J=13.2, 3.8 Hz, 1H),3.32 (dd, J=13.2, 10.0 Hz, 1H), 3.05, 3.00 (ABq, JAB=12.5 Hz, 2H), 1.08(s, 9H).

Example 30:(R)-1-(3-fluorophenyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)ethan-1-olhydrochloride

A mixture of (R)-2-(3-fluorophenyl)oxirane (60 mg, 0.43 mmol) and1-trifluoromethyl-1-cyclopropylamine (54 mg, 0.43 mmol) was heated at75° C. overnight. Another portion of1-trifluoromethyl-1-cyclopropylamine (54 mg, 0.43 mmol) and DMF (0.33mL) was added and the heating was continued. H₂O (77 μL, 4.3 mmol) and1-trifluoromethyl-1-cyclopropylamine (54 mg, 0.43 mmol) was added andheating was continued for 3 d adding portions of1-trifluoromethyl-1-cyclopropylamine (54 mg, 0.43 mmol) each day. [Thetotal amount of the 1-trifluoromethyl-1-cyclopropylamine was (326 mg,2.60 mmol)]. The mixture was concentrated and dissolved in Et₂O (2 mL).HCl (2 M in Et₂O, 0.21 mL, 0.43 mmol) was added and the solids werecollected and dried to give the title compound (20 mg, 67 pmol, 15%).

¹H NMR (400 MHz, CD₃OD): δ 7.45-7.39 (m, 1H), 7.28-7.20 (m, 2H),7.12-7.05 (m, 1H), 4.99 (dd, J=10.4, 3.1 Hz, 1H), 3.47 (dd, J=12.7, 3.4Hz, 1H), 3.33-3.25 (m, 1H, overlapping with CD₃OD), 1.65-1.44 (m, 4H).

Example 31:(R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-olhydrochloride

(a) N-(2,6-difluoro-3-methylphenyl)acetamide

The sub-title compound was prepared from 2,6-difluoro-3-methylaniline inaccordance with the procedure in Example 6, Step (a).

(b) 3-acetamido-2,4-difluorobenzoic acid

The sub-title compound was prepared fromN-(2,6-difluoro-3-methylphenyl)acetamide in accordance with theprocedure in Example 7, Step (b).

(c) N-(3-(2-Chloroacetyl)-2,6-difluorophenyl)acetamide

A mixture of 3-acetamido-2,4-difluorobenzoic acid (250 mg, 1.16 mmol)and SOCl₂ (2.6 mL) was heated at 60° C. for 4 h and allowed to cool.Toluene was added and the mixture concentrated. The procedure of addingtoluene followed by concentration was repeated three times. The residuewas dissolved in CH₂Cl₂ and trimethylsilyl diazomethane (1.16 mL, 2.32mmol) was added dropwise at 0° C. The mixture was allowed to come to rtover 18 h and cooled to 0° C. HCl (4 M in dioxane, 1.45 mL, 5.81 mmol)was added dropwise. The mixture was allowed to come to rt over 1 h,diluted with EtOAc and washed with Na₂CO₃ (aq, sat), dried over MgSO₄and concentrated. The residue was purified by chromatography to give thesub-title compound (198 mg, 0.80 mmol, 69%).

(d) (R)—N-(3-(2-chloro-1-hydroxyethyl)-2,6-difluorophenyl)acetamide

RhClCp*[(1S,2S)-p-TsNCH(C₆H₅)CH(C₆H₅)NH₂]/HCl.Et₃N (5.02 mg, 0.0065mmol), prepared from dichloro(pentamethylcyclopentadienyl)rhodium (III)dimer, (1S, 2S)-(+)—N-(4-toluenesulphonyl)-1,2-diphenylethylene diamineand Et₃N as described in WO 2008/054155, was added to a mixture ofN-(3-(2-chloroacetyl)-2,6-difluorophenyl)acetamide (160 mg, 0.65 mmol)in DMF (2.7 mL). Formic acid/Et₃N (5:2, 0.90 mL) was added and themixture was stirred at rt for 20 min. The mixture was diluted withEtOAc, washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was crystallized from CH₂Cl₂/hexane to givethe sub-title compound (101 mg, 0.41 mmol, 63%, ee=97%).

(e)(R)—N-(3-(2-(tert-butylamino)-1-hydroxyethyl)-2,6-difluorophenyl)acetamide

The sub-title compound was prepared from(R)—N-(3-(2-chloro-1-hydroxyethyl)-2,6-difluorophenyl)acetamide inaccordance with the procedure in Example 25, Step (d).

(f) (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-olhydrochloride

NaOH (aq, 10%, 0.52 mL) was added to of(R)—N-(3-(2-(tert-butylamino)-1-hydroxyethyl)-2,6-difluorophenyl)acetamide(52 mg, 0.18 mmol) in EtOH (0.52 mL) and the mixture was heated at 75°C. for 20 h. The EtOH was removed in vacuo and the residue extractedwith CH₂Cl₂. The combined extracts were washed with water, dried overNa₂SO₄, filtered and concentrated. The residue was dissolved in Et₂O.HCl (2 M in Et₂O, 0.13 mL, 0.27 mmol) was added. The solids werecollected and dried to give the title compound (32 mg, 0.11 mmol, 63%).

¹H NMR (400 MHz, D₂O): δ 7.11-7.01 (m, 2H), 5.29-5.15 (dd, J=9.6, 3.2Hz, 1H), 3.36-3.23 (m, 2H), 1.40 (s, 9H).

Example 32:(R)-2-(tert-butylamino)-1-(3-fluoro-2-methylphenyl)ethan-1-ol

N,N′-bis[(11bS)-3,5-dihydro-3,5-dimethyl-4-oxido-4H-dinaphtho[2,1-d:1′,2′-f]-[1,3,2]diazaphosphepin-4-yl]-N,N′-dimethyl-1,5-pentanediamine (15 mg, 18 pmol)and freshly distilled SiCl₄ (45.6 μL, 0.40 mmol) were added to3-fluoro-2-methylbenzaldehyde (50 mg, 0.36 mmol) in CH₂Cl₂ (0.34 mL) at−78° C. A solution of tert-butylisocyanide (49.1 μL, 0.43 mmol) inCH₂Cl₂ (0.34 mL) was added over 4 h at −78° C. and the mixture wasstirred at at −78° C. for 2 h. BH₃NH₃ (22.3 mg, 0.72 mmol) was added andthe cooling-bath was removed and the mixture stirred for 1 h at rt anddiluted with CH₂Cl₂ (2.5 mL). The mixture was added cautiously [gasevolution] to Na₂CO₃ (aq, 10%, 5 mL), stirred at rt for 30 min andfiltered throug Celite. The solids were washed with CH₂Cl₂ (5 mL) andthe aq phase was collected and extracted with CH₂Cl₂. The combinedorganic phases were dried (Na₂SO₄) and concentrated. The residue waspurified by chromatography to give the title compound (53 mg, 0.24 mmol,65%).

¹H NMR (400 MHz, CDCl₃): δ 7.32 (d, J=7.6 Hz, 1H), 7.23-7.13 (m, 1H),6.96-6.91 (m, 1H), 4.79 (dd, J=8.8, 3.6 Hz, 1H), 2.88 (dd, J=12.4, 3.6Hz, 1H), 2.49 (dd, J=12.0, 8.8 Hz, 1H), 2.22 (d, J=1.6 Hz, 3H), 1.11 (s,9H).

BIOLOGICAL EXAMPLES

L6-myoblasts were grown in Dulbecco's Modified Eagle's Medium (DMEM)containing 4.5 g/l glucose supplemented with 10% fetal bovine serum, 2mM L-Glutamine, 50 U/ml penicillin, 50 μg/ml streptomycin and 10 mMHEPES. Cells were plated at 1×10⁵ cells per ml in 24-well plates. Afterreaching 90% confluence the cells were grown in medium containing 2% FBSfor 7 days where upon cells differentiated into myotubes.

Biological Example 1: Glucose Uptake

Differentiated L6-myotubes were serum-starved over night in mediumcontaining 0.5% fatty-acid free BSA and stimulated with agonist, finalconcentration 1×10⁻⁵. After 1 h 40 min cells were washed with warm,glucose free medium or PBS and another portion of agonist was added toglucose free medium. After 20 min the cells were exposed to 50 nM³H-2-deoxy-glucose for another 10 min before washed in ice cold glucosefree medium or PBS and lysed in 0.2 M NaOH for 1 h in 60° C. Cell lysatewas mixed with scintillation buffer (Emulsifier Safe, Perkin Elmer andradioactivity detected in a β-counter (Tri-Carb 2800TR, Perkin Elmer).The activity for each compound is compared to that of isoproterenol. Ifa compound shows activity of more than 75% of that of isoprenaline, theactivity is denoted with +++, if it is between 75 and 50% it is denotedwith ++; if it is between 50 and 25% it is denoted with +; if it lessthan 25% it is denoted with −.

Biological Example 2: Measurement of Intracellular cAMP Levels

Differentiated cells were serum-starved over night and stimulated withagonist, final concentration 1×10⁻⁵, for 15 min in stimulation buffer(HBSS supplemented with 1% BSA, 5 mM HEPES and 1 mM IBMX, pH 7.4). Themedium was then aspirated and to end the reaction 100 μL of 95% EtOH wasadded to each well of a 24-well plate and cells were kept in −20° C.over night. The EtOH was let to evaporate and 500 μL of lysis buffer (1%BSA, 5 mM HEPES and 0.3% Tween-20, pH 7.4) was added to each well beforeput in −80° C. for 30 min and then kept in −20° C. Intracellular cAMPlevels were detected using an alpha screen cAMP kit (6760635D fromPerkin Elmer). The activity for each compound is compared to that ofisoproterenol. If a compound shows activity of more than 75% of that ofisoprenaline, the activity is denoted with +++, if it is between 75 and50% it is denoted with ++; if it is between 50 and 25% it is denotedwith +; if it less than 25% it is denoted with −.

Using the assays described in Biological Examples 1 and 2 the followingresults were obtained.

Compound Biological Biological example no. example 1 example 2 1 ++ − 2++ − 3 + − 4 +++ − 5 +++ − 6 +++ +++ 7 +++ − 8 + − 9 ++ − 10 ++ − 11 + −12 +++ − 13 ++ − 14 +++ − 15 +++ + 16 +++ − 17 ++ − 18 +++ − 19 ++ − 20+++ − 21 +++ + 22 +++ − 23 +++ ++ 24 +++ − 25 ++ ++ 26 +++ + 27 +++ + 28++ − 29 + − 30 ++ − 31 +++ − 32 +++ −

The invention claimed is:
 1. A pharmaceutical composition comprising(R)-2-(tert-Butylamino)-1-(3-fluorophenyl)ethan-1-ol, having thestructure:

or a pharmaceutically acceptable salt thereof, and optionally one ormore pharmaceutically acceptable adjuvant, diluent and/or carrier;wherein the (R)-2-(tert-Butylamino)-1-(3-fluorophenyl)ethan-1-ol ispresent in an enanteromeric excess of at least 90%.
 2. A method oftreating hyperglycaemia or a disorder characterized by hyperglycaemiacomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound as defined in claim 1, or apharmaceutically acceptable salt thereof.
 3. The method according toclaim 2, wherein the hyperglycaemia or a disorder characterized byhyperglycaemia is type 2 diabetes.
 4. The method according to claim 2,wherein the patient displays severe insulin resistance.
 5. The methodaccording to claim 2, wherein the disorder characterised byhyperglycaemia is selected from the group consisting ofRabson-Mendenhall syndrome, Donohue's syndrome (leprechaunism), Type Aand Type B syndromes of insulin resistance, the HAIR-AN(hyperandrogenism, insulin resistance, and acanthosis nigricans)syndromes, pseudoacromegaly, and lipodystrophy.